2&#39;-substituted 1,1&#39;-biphenyl-2-carboxamides, process for their preparation, their use as medicaments, and pharmaceutical preparations comprising them

ABSTRACT

Compounds of the formula I,  
                 
 
     in which R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30) and R(31) have the meanings indicated in the claims, are very particularly suitable as novel and antiarrythmic active compounds, in particular for the treatment and prophylaxis of atrial arrythmias, e.g. atrial fibrillation (AF), or atrial flutter.

[0001] This application is a continuation-in-part of co-pendingapplication Ser No. 09/675,674, filed on Sep. 29, 2000.

[0002] This application claims the benefit of foreign priority under 35U.S.C. §119 to German patent application no. 19947457.5, filed on Oct.2, 1999, the contents of which are incorporated by reference herein.

[0003] The invention relates to compounds of the formula I,

[0004] in which R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30)and R(31) have the meanings indicated below, their preparation and theiruse, in particular in pharmaceuticals.

[0005] The compounds of the formula I according to the invention werehitherto unknown. They act on the so-called Kv1.5 potassium channel andinhibit a potassium current described as “ultra-rapidly activatingdelayed rectifier” in the human atrium. The compounds are therefore veryparticularly suitable as novel antiarrhythmic active compounds, inparticular for the treatment and prophylaxis of atrial arrhythmias, e.g.atrial fibrillation (AF) or atrial flutter.

[0006] The compounds can be used for the termination of existing atrialfibrillation or flutter to restore sinus rhythm (cardioversion).Furthermore the compounds reduce the incidence for the development ofnew episodes of fibrillation (maintenance of sinus rhythm, prophylaxis).

[0007] Atrial fibrillation (AF) and atrial flutter are the most frequentpersistent cardiac arrhythmias. The occurrence increases with increasingage and frequently leads to fatal sequelae, such as, for example,cerebral apoplexy. AF affects about 1 million Americans annually andleads to more than 80,000 strokes each year in the USA. The presentlycustomary antiarrhythmics of classes I and III, reduce the reoccurrencerate of AF, but because of their potential proarrhythmic side effectsonly have restricted use. There is therefore a great medical need forthe development of better medicaments for the treatment of atrialarrhythmias (S. Nattel, Am. Heart J. 130, 1995, 1094-1106; “Newerdevelopments in the management of atrial fibrillation”).

[0008] It was shown that most supraventricular arrhythmias are subjectto so-called “reentry” excitatory waves. Such reentries occur when thecardiac tissue has a slow conductivity and at the same time very shortrefractory periods. The increasing of the myocardial refractory time byprolongation of the action potential is a recognized mechanism forending arrhythmias or preventing their formation (T. J. Colatsky et al.,Drug Dev. Res. 19, 1990, 129-140; “Potassium channels as targets forantiarrhythmic drug action”). The length of the action potential isessentially determined by the extent of repolarizing K⁺ currents whichflow out of the cell via various K⁺ channels. Particularly greatimportance is ascribed here to the so-called “delayed rectifier” I_(K),which consists of 3 different components: IK_(r), IK_(s) and IK_(ur).

[0009] Most known class III antiarrhythmics (e.g. dofetilide, E4031 andd-sotalol) mainly or exclusively block the rapidly activating potassiumchannel IK_(r), which can be detected both in cells of the humanventricle and in the atrium. However, it has been shown that at low ornormal heart rates these compounds have an increased proarrhythmic risk,arrhythmias which are described as “Torsades de pointes” being observedin particular (D. M. Roden, Am. J. Cardiol. 72, 1993, 44B-49B; “Currentstatus of class III antiarrhythmic drug therapy”). In addition to thishigh, in some cases fatal, risk at low frequency, a decrease in theefficacy under the conditions of tachycardia, in which the action isespecially needed, has been found for the I_(Kr) blockers (“negativeuse-dependence”).

[0010] While some of these disadvantages can possibly be overcome byblockers of the slowly activating components (IK_(s)), their efficacyhas hitherto not been confirmed, as no clinical investigations withIK_(s) channel blockers are known.

[0011] The “particularly rapidly” activating and very slowlyinactivating component of the delayed rectifier IK_(ur) (=ultra-rapidlyactivating delayed rectifier), which corresponds to the Kv1.5 channel,plays a particularly large role in the repolarization period in thehuman atrium. In comparison to the inhibition of IK_(r) or IK_(s),inhibition of the IK_(ur) potassium outward current is thus aparticularly effective method for the prolongation of the atrial actionpotential and thus for the ending or prevention of atrial arrhythmias.Mathematical models of the human action potential suggest that thepositive effect of a blockade of the IK_(ur), especially under thepathological conditions of chronic atrial fibrillation, should beparticularly pronounced (M. Courtemanche, R. J. Ramirez, S. Nattel,Cardiovascular Research 1999, 42, 477-489: “Ionic targets for drugtherapy and atrial fibrillation-induced electrical remodeling: insightsfrom a mathematical model”).

[0012] In contrast to IK_(r a)nd IK_(s), which also occur in the humanventricle, the IK_(ur) admittedly plays an important role in the humanatrium, but not in the ventricle. For this reason, on inhibition of theIK_(ur) current in contrast to the blockade of IK_(r) or IK_(s), therisk of a proarrhythmic action on the ventricle is excluded from thestart (Z. Wang et al., Circ. Res. 73, 1993, 1061-1076: “SustainedDepolarisation-Induced Outward Current in Human Atrial Myocytes”; G. -R.Li et al, Circ. Res. 78, 1996, 689-696: “Evidence for Two Components ofDelayed Rectifier K⁺ Current in Human Ventricular Myocytes”; G. J. Amoset al., J. Physiol. 491, 1996, 31-50: “Differences between outwardcurrents of human atrial and subepicardial ventricular myocytes”).

[0013] Antiarrhythmics which act via a selective blockade of the IK_(ur)current or Kv1.5 channel were previously not available, however, on themarket. For numerous pharmaceutical active compounds (e.g. tedisamil,bupivacaine or sertindole), a blocking action on the Kv1.5 channel wasadmittedly described, but the Kv1.5 blockade here in each caserepresents only a side effect next to other principal actions of thesubstances.

[0014] WO 98 04 521 claims aminoindans as potassium channel blockerswhich block the Kv1.5 channel. The applications WO 98 18 475 and WO 9818 476 claim the use of various pyridazinones and phosphine oxides asantiarrhythmics, which should act via a blockade of the IK_(ur).However, the same compounds were originally also described asimmuno-suppressants (WO 96 25 936). The compounds described in thesementioned applications are structurally completely different to thecompounds according to the invention of this application.

[0015] It has now surprisingly been found that the 2′-substituted1,1′-biphenyl-2-carboxamides described here are potent blockers of thehuman Kv1.5 channel. They can therefore be used as novel antiarrhythmicshaving a particularly advantageous safety profile. In particular, thecompounds are suitable for the treatment of supraventriculararrhythmias, e.g. atrial fibrillation or atrial flutter.

[0016] The compounds according to the invention were previously unknown.Some structurally related compounds are described in Helv. Chim. Acta1994 (70) 70 and references cited there. For the peptide compoundsdescribed there (e.g. compound A), however, no potassiumchannel-blocking activity is known. Moreover, compounds of this typeshould have too low a metabolic stability for use as antiarrhythmics onaccount of the numerous peptide bonds.

[0017] A further similar compound (compound B) is mentioned in EuropeanPatent Application EP 0620216. The compound B and all other compounds ofthis application carry, in the position of R(3), a specific substituent(e.g. benzoyl-1,2,3,4-tetrahydroisoquinoline), which is not included inthe compounds according to the invention of this application. Thecompounds mentioned in EP 0 620 216 act as vasopressin antagonists andthus have a completely different biological activity to the blockers ofthe Kv1.5 channel described here.

[0018] The present invention relates to compounds of the formula I

[0019] in which:

[0020] R(1) is C(O)OR(9), SO₂R(10), COR(11), C(O)NR(12)R(13) orC(S)NR(12)R(13);

[0021] R(9) is C_(x)H_(2x)—R(14);

[0022] x is 0, 1, 2, 3or 4,

[0023] where x cannot be 0 if R(14) is OR(15) or SO₂Me;

[0024] R(14) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkylhaving 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF₃, OCF₃, C₂F₅,C₃F₇, CH₂F, CHF₂, OR(15), SO₂Me, phenyl, naphthyl, biphenylyl, furyl,thienyl or an N-containing heteroaromatic having 1, 2, 3, 4, 5, 6, 7, 8or 9 carbon atoms,

[0025] where phenyl, naphthyl, biphenylyl, furyl, thienyl and theN-containing hetero-aromatic are unsubstituted or substituted by 1, 2 or3 substituents selected from the group consisting of F, Cl, Br, I, OCF₃,CF₃, NO₂, CN, COOMe, CONH₂, COMe, NH₂, OH, alkyl having 1, 2, 3 or 4carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino,sulfamoyl, methylsulfonyl and methylsulfonylamino;

[0026] R(15) is alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkylhaving 3, 4, 5 or 6 carbon atoms, CF₃ or phenyl which is unsubstitutedor substituted by 1, 2 or 3 substituents selected from the groupconsisting of F, Cl, Br, I, CF₃, NO₂, CN, COOMe, CONH₂, COMe, NH₂, OH,alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl andmethylsulfonylamino;

[0027] R(10), R(11) and R(12)

[0028] independently of one another are defined as R(9);

[0029] R(13) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF₃;

[0030] R(2) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF₃;

[0031] R(3) is C_(y)H_(2y)—R(16);

[0032] y is 0, 1, 2, 3 or 4, where y cannot be 0 if R(16) is OR(17) orSO₂Me;

[0033] R(16) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, cycloalkylhaving 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbon atoms, CF₃, C₂F₅, C₃F₇,CH₂F, CHF₂, OR(17), SO₂Me, phenyl, naphthyl, furyl, thienyl or anN-containing heteroaromatic having 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbonatoms,

[0034] where phenyl, naphthyl, furyl, thienyl and the N-containingheteroaromatic are unsubstituted or substituted by 1, 2 or 3substituents selected from the group consisting of F, Cl, Br, I, CF₃,OCF₃, NO₂, CN, COOMe, CONH₂, COMe, NH₂, OH, alkyl having 1, 2, 3 or 4carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino,sulfamoyl, methylsulfonyl and methylsulfonylamino;

[0035] R(17) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms,cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF₃, phenyl or 2-, 3- or4-pyridyl,

[0036] where phenyl or 2-, 3- or 4-pyridyl are unsubstituted orsubstituted by 1, 2 or 3 substituents selected from the group consistingof F, Cl, Br, I, CF₃, OCF₃, NO₂, CN, COOMe, CONH₂, COMe, NH₂, OH, alkylhaving 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbonatoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

[0037] or

[0038] R(3) is CHR(18)R(19);

[0039] R(18) is hydrogen or C_(z)H_(2z)—R(16), where R(16) is defined asindicated above;

[0040] z is 0, 1, 2or 3;

[0041] R(19) is COOH, CONH₂, CONR(20)R(21), COOR(22), CH₂OH;

[0042] R(20) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms,C_(v)H_(2v)—CF₃ or C_(w)H_(2w)-phenyl,

[0043] where the phenyl ring is unsubstituted or substituted by 1, 2 or3 substitutents selected from the group consisting of F, Cl, Br, I, CF₃,OCF₃, NO₂, CN, COOMe, CONH₂, COMe, NH₂, OH, alkyl having 1, 2, 3 or 4carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino,sulfamoyl, methylsulfonyl and methylsulfonylamino;

[0044] v is 0, 1, 2 or 3;

[0045] w is 0, 1, 2 or 3;

[0046] R(21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;

[0047] R(22) is alkyl having 1, 2, 3, 4 or 5 carbon atoms;

[0048] R(4) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms orCF₃;

[0049] or

[0050] R(3) and R(4)

[0051] together are a chain of 4 or 5 methylene groups, of which onemethylene group can be replaced by —O—, —S—, —NH—, —N(methyl)- or—N(benzyl)-;

[0052] R(5), R(6), R(7) and R(8)

[0053] independently of one another are hydrogen, F, Cl, Br, I, CF₃,NO₂, CN, COOMe, CONH₂, COMe, NH₂, OH, alkyl having 1, 2, 3 or 4 carbonatoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino,sulfamoyl, methylsulfonyl or methylsulfonylamino;

[0054] R(30) and R(31)

[0055] independently of one another hydrogen or alkyl having 1, 2 or 3carbon atoms;

[0056] or

[0057] R(30) and R(31)

[0058] together form a chain of 2 methylene groups;

[0059] and their pharmaceutically acceptable salts.

[0060] Preferred compounds of the formula I are those in which:

[0061] R(1) is C(O)OR(9), SO₂R(10), COR(11) or C(O)NR(12)R(13);

[0062] R(9) is C_(x)H_(2x)—R(14);

[0063] x is 0, 1, 2, 3 or 4,

[0064] where x cannot be 0 if R(14) is OR(15);

[0065] R(14) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkylhaving 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF₃, C₂F₅, OR(15), phenyl,furyl, thienyl or an N-containing heteroaromatic having 1, 2, 3, 4, 5,6, 7, 8 or 9 carbon atoms,

[0066] where phenyl, furyl, thienyl and the N-containing heteroaromaticare unsubstituted or substituted by 1, 2 or 3 substituents selected fromthe group consisting of F, Cl, Br, CF₃, OCF₃, NO₂, CN, COOMe, CONH₂,COMe, NH₂, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1,2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl andmethylsulfonylamino;

[0067] R(15) is alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkylhaving 3, 4, 5 or 6 carbon atoms, CF₃ or phenyl,

[0068] which is unsubstituted or substituted by 1, 2 or 3 substituentsselected from the group consisting of F, Cl, Br, CF₃, NO₂, CN, COOMe,CONH₂, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl andmethylsulfonylamino;

[0069] R(10), R(11) and R(12)

[0070] independently of one another are defined as R(9);

[0071] R(13) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF₃;

[0072] R(2) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF₃;

[0073] R(3) is C_(y)H_(2y)—R(16);

[0074] y is 0, 1, 2, 3 or 4,

[0075] where y cannot be 0 if R(16) is OR(17);

[0076] R(16) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkylhaving 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF₃, C₂F₅, OR(17), phenyl,furyl, thienyl or an N-containing heteroaromatic having 1, 2, 3, 4, 5,6, 7, 8 or 9 carbon atoms,

[0077] where phenyl, furyl, thienyl and the N-containing heteroaromaticare unsubstituted or substituted by 1, 2 or 3 substituents selected fromthe group consisting of F, Cl, Br, CF₃, OCF₃, NO₂, CN, COOMe, CONH₂,COMe, NH₂, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1,2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl andmethylsulfonylamino;

[0078] R(17) is alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkylhaving 3, 4, 5 or 6 carbon atoms, CF₃, phenyl or 2-, 3-, or 4-pyridyl,

[0079] where phenyl or 2-, 3- or 4-pyridyl are unsubstituted orsubstituted by 1, 2 or 3 substituents selected from the group consistingof F, Cl, Br, CF₃, OCF₃, NO₂, CN, COOMe, CONH₂, COMe, OH, alkyl having1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

[0080] or

[0081] R(3) is CHR(18)R(19);

[0082] R(18) is hydrogen or C_(z)H_(2z)—R(16), where R(16) is defined asindicated above;

[0083] z is 0, 1, 2 or 3;

[0084] R(19) is CONH₂, CONR(20)R(21), COOR(22), CH₂OH;

[0085] R(20) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms,C_(v)H_(2v)—CF₃ or C_(w)H_(2w)-phenyl,

[0086] where the phenyl ring is unsubstituted or substituted by 1, 2 or3 substituents selected from the group consisting of F, Cl, Br, CF₃,OCF₃, NO₂, CN, COOMe, CONH₂, COMe, NH₂, OH, alkyl having 1, 2, 3 or 4carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino,sulfamoyl, methylsulfonyl and methylsulfonylamino;

[0087] v is 0, 1, 2 or 3;

[0088] w is 0, 1, 2 or 3;

[0089] R(21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;

[0090] R(22) is alkyl having 1, 2, 3, 4 or 5 carbon atoms;

[0091] R(4) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms orCF₃;

[0092] R(5), R(6), R(7) and R(8)

[0093] independently of one another are hydrogen, F, Cl, Br, CF₃, NO₂,CN, COOMe, CONH₂, COMe, NH₂, OH, alkyl having 1, 2, 3 or 4 carbon atoms,alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl,methylsulfonyl or methylsulfonylamino;

[0094] R(30) and R(31)

[0095] independently of one another hydrogen or alkyl having 1, 2 or 3carbon atoms;

[0096] or

[0097] R(30) and R(31)

[0098] together form a chain of 2 methylene groups;

[0099] and their pharmaceutically acceptable salts.

[0100] Particularly preferred compounds of the formula I are those inwhich:

[0101] R(1) is C(O)OR(9), SO₂R(10), COR(11) or C(O)NR(12)R(13);

[0102] R(9) is C_(x)H_(2x)—R(14);

[0103] x is 0, 1, 2, 3 or 4,

[0104] where x cannot be 0 if R(14) is OR(15);

[0105] R(14) is cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms,CF₃, OR(15), phenyl, furyl, thienyl or an N-containing heteroaromatichaving 3, 4 or 5 carbon atoms,

[0106] where phenyl, furyl, thienyl and the N-containing heteroaromaticare unsubstituted or substituted by 1 or 2 substituents selected fromthe group consisting of F, Cl, Br, CF₃, OCF₃, CN, COOMe, CONH₂, COMe,OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbonatoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

[0107] R(15) is alkyl having 1 or 2 carbon atoms, cycloalkyl having 3,4, 5 or 6 carbon atoms, CF₃ or phenyl,

[0108] which is unsubstituted or substituted by 1 or 2 substituentsselected from the group consisting of F, Cl, Br, CF₃, CN, COOMe, CONH₂,COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl andmethylsulfonylamino;

[0109] R(10), R(11) and R(12)

[0110] independently of one another are defined as R(9);

[0111] R(13) is hydrogen;

[0112] R(2) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

[0113] R(3) is CHR(18)R(19);

[0114] R(18) is hydrogen or C_(z)H_(2z)—R(16);

[0115] z is 0, 1, 2 or 3;

[0116] R(19) is CONH₂, CONR(20)R(21), COOR(22) or CH₂OH;

[0117] R(20) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbon atoms,C_(v)H_(2v)—CF₃ or C_(w)H_(2w)-phenyl,

[0118] where the phenyl ring is unsubstituted or substituted by 1, 2 or3 substituents selected from the group consisting of F, Cl, Br, CF₃,OCF₃, CN, COOMe, CONH₂, COMe, OH, alkyl having 1, 2 or 3 carbon atoms,alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl,methylsulfonyl and methylsulfonylamino;

[0119] v is 0, 1, 2 or 3;

[0120] w is 0, 1, 2 or 3;

[0121] R(21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;

[0122] R(22) is alkyl having 1, 2, 3, 4 or 5 carbon atoms;

[0123] R(16) is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF₃, OR(17), phenyl, furyl, thienylor an N-containing heteroaromatic having 3, 4 or 5 carbon atoms,

[0124] where phenyl, furyl, thienyl and the N-containing heteroaromaticare unsubstituted or substituted by 1 or 2 substitutents selected fromthe group consisting of F, Cl, Br, CF₃, OCF₃, CN, COOMe, CONH₂, COMe,NH₂, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl andmethylsulfonylamino;

[0125] R(17) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkylhaving 3, 4, 5 or 6 carbon atoms, CF₃, phenyl or 2-, 3- or 4-pyridyl,

[0126] where phenyl or 2-, 3- or 4-pyridyl are unsubstituted orsubstituted by 1, 2 or 3 substituents selected from the group consistingof F, Cl, Br, CF₃, OCF₃, CN, COOMe, CONH₂, COMe, OH, alkyl having 1, 2,3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

[0127] R(4) is hydrogen or alkyl having 1 or 2 carbon atoms;

[0128] R(5), R(6), R(7) and R(8)

[0129] independently of one another are hydrogen, F, Cl, Br, CF₃, CN,COOMe, CONH₂, COMe, NH₂, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxyhaving 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl ormethylsulfonylamino;

[0130] R(30) and R(31)

[0131] independently of one another hydrogen or methyl;

[0132] or

[0133] R(30) and R(31)

[0134] together form a chain of 2 methylene groups;

[0135] and their pharmaceutically acceptable salts.

[0136] Particularly preferred compounds of the formula I are also thosein which:

[0137] R(1) is C(O)OR(9), SO₂R(10), COR(11) or C(O)NR(12)R(13);

[0138] R(9) is C_(x)H_(2x)—R(14);

[0139] x is 0, 1, 2, 3 or 4,

[0140] where x cannot be 0 if R(14) is OR(15);

[0141] R(14) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkylhaving 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF₃, OR(15), phenyl, furyl,thienyl or an N-containing heteroaromatic having 3, 4 or 5 carbon atoms,

[0142] where phenyl, furyl, thienyl and the N-containing heteroaromaticare unsubstituted or substituted by 1 or 2 substituents selected fromthe group consisting of F, Cl, Br, CF₃, OCF₃, CN, COOMe, CONH₂, COMe,OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbonatoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

[0143] R(15) is alkyl having 1 or 2 carbon atoms, cycloalkyl having 3,4, 5 or 6 carbon atoms, CF₃ or phenyl,

[0144] which is unsubstituted or substituted by 1 or 2 substituentsselected from the group consisting of F, Cl, Br, CF₃, CN, COOMe, CONH₂,COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl andmethylsulfonylamino;

[0145] R(10), R(11) and R(12)

[0146] independently of one another are defined as R(9);

[0147] R(13) is hydrogen;

[0148] R(2) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;

[0149] R(3) is C_(y)H_(2y)—R(16);

[0150] y is 0, 1, 2, 3 or 4,

[0151] where y cannot be 0 if R(16) is OR(17);

[0152] R(16) is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF₃, OR(17), phenyl, furyl, thienylor an N-containing heteroaromatic having 3, 4 or 5 carbon atoms,

[0153] where phenyl, furyl, thienyl and the N-containing heteroaromaticare unsubstituted or substituted by 1 or 2 substituents selected fromthe group consisting of F, Cl, Br, CF₃, OCF₃, CN, COOMe, CONH₂, COMe,NH₂, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl andmethylsulfonylamino;

[0154] R(17) is alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkylhaving 3, 4, 5 or 6 carbon atoms, CF₃, phenyl or 2-, 3- or 4-pyridyl,

[0155] where phenyl or 2-, 3- or 4-pyridyl are unsubstituted orsubstituted by 1, 2 or 3 substituents selected from the group consistingof F, Cl, Br, CF₃, OCF₃, NO₂, CN, COOMe, CONH₂, COMe, OH, alkyl having1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;

[0156] R(4) is hydrogen or alkyl having 1 or 2 carbon atoms;

[0157] R(5), R(6), R(7) and R(8)

[0158] independently of one another are hydrogen, F, Cl, Br, CF₃, CN,COOMe, CONH₂, COMe, NH₂, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxyhaving 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl ormethylsulfonylamino;

[0159] R(30) and R(31)

[0160] independently of one another hydrogen or methyl;

[0161] or

[0162] R(30) and R(31)

[0163] together form a chain of 2 methylene groups;

[0164] and their pharmaceutically acceptable salts.

[0165] Very particularly preferred compounds of the formula I are thosein which:

[0166] R(1) is C(O)OR(9), SO₂R(10), COR(11) or C(O)NR(12)R(13);

[0167] R(9) is C_(x)H_(2x)—R(14);

[0168] x is 0, 1, 2 or 3;

[0169] R(14) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkylhaving 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF₃, phenyl or pyridyl,

[0170] where phenyl and pyridyl are unsubstituted or substituted by 1 or2 substituents selected from the group consisting of F, Cl, CF₃, OCF₃,OH, alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2 carbonatoms;

[0171] R(10), R(11) and R(12)

[0172] independently of one another are defined as R(9);

[0173] R(13) is hydrogen;

[0174] R(2) is hydrogen;

[0175] R(3) is C_(y)H_(2y)—R(16);

[0176] y is 0, 1 or 2;

[0177] R(16) is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 5or 6 carbon atoms, CF₃, phenyl or pyridyl,

[0178] where phenyl and pyridyl are unsubstituted or substituted by 1 or2 substituents selected from the group consisting of F, Cl, CF₃, OCF₃,OH, alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2 carbonatoms;

[0179] R(4) is hydrogen;

[0180] R(5), R(6), R(7) and R(8)

[0181] independently of one another are hydrogen, F, CF₃, CN, COOMe,CONH₂, NH₂, OH, alkyl having 1, 2 or 3 carbon atoms or alkoxy having 1or 2 carbon atoms;

[0182] R(30) and R(31)

[0183] independently of one another hydrogen or methyl;

[0184] or

[0185] R(30) and R(31)

[0186] together form a chain of 2 methylene groups;

[0187] and their pharmaceutically acceptable salts.

[0188] Especially preferred compounds of the formula I are those inwhich:

[0189] R(1) is C(O)OR(9) or COR(11);

[0190] R(9) is C_(x)H_(2x)—R(14);

[0191] x is 0, 1, 2 or 3;

[0192] R(14) is cycloalkyl having 5 or 6 carbon atoms or phenyl,

[0193] where phenyl is unsubstituted or substituted by 1 or 2substituents selected from the group consisting of F, Cl, CF₃, OCF₃,alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2 carbonatoms;

[0194] R(11) is defined as R(9);

[0195] R(2) is hydrogen;

[0196] R(3) is C_(y)H_(2y)—R(16);

[0197] y is 0, 1 or 2;

[0198] R(16) is alkyl having 1, 2 or 3 carbon atoms, cycloalkyl having 5or 6 carbon atoms, CF₃, phenyl or pyridyl

[0199] where phenyl and pyridyl are unsubstituted or substituted by 1 or2 substituents selected from the group consisting of F, Cl, CF₃, OCF₃,alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2 carbonatoms;

[0200] R(4) is hydrogen;

[0201] R(5), R(6), R(7) and R(8)

[0202] independently of one another are hydrogen, F, CF₃, alkyl having1, 2 or 3 carbon atoms or alkoxy having 1 or 2 carbon atoms;

[0203] R(30) and R(31)

[0204] are hydrogen;

[0205] and their pharmaceutically acceptable salts.

[0206] Alkyl radicals and alkylene radicals can be straight-chain orbranched. This also applies to the alkylene radicals of the formulaeC_(x)H_(2x), C_(y)H_(2y), C_(z)H_(2z), C_(v)H_(2v) and C_(w)H_(2w).Alkyl radicals and alkylene radicals can also be straight-chain orbranched if they are substituted or are contained in other radicals,e.g. in an alkoxy radical or in a fluorinated alkyl radical. Examples ofalkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl,n-hexyl, 3,3-dimethyl-butyl, heptyl, octyl, nonyl, decyl, undecyl,dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl,octadecyl, nonadecyl, eicosyl. The divalent radicals derived from theseradicals, e.g. methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene,1,2-propylene, 2,2-propylene, 1,3-propylene, 1,1-butylene, 1,4-butylene,1,5-pentylene, 2,2-dimethyl-1,3-propylene, 1,6-hexylene, etc., areexamples of alkylene radicals.

[0207] Cycloalkyl radicals can likewise be branched. Examples ofcycloalkyl radicals having 3 to 11 carbon atoms are cyclopropyl,cyclobutyl, 1-methylcyclopropyl, 2-methylcyclopropyl, cyclopentyl,2-methylcyclobutyl, 3-methylcyclobutyl, cyclopentyl, cyclohexyl,2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, menthyl,cycloheptyl, cyclooctyl etc.

[0208] N-containing heteroaromatics having 1, 2, 3, 4, 5, 6, 7, 8 or 9carbon atoms are considered in particular as 1-, 2- or 3-pyrrolyl, 1-,2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 1,2,3-triazol-1-, -4-or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 2-, 4- or5-oxazolyl, 3-, 4- or 5-isoxazolyl, 1,2,3-oxadiazol-4- or -5-yl,1,2,4-oxadiazol-3- or -5-yl, 1,3,4-oxadiazol-2-yl or -5-yl, 2-, 4- or5-thiazolyl, 3-, 4- or 5-isothiazolyl, 1,3,4-thiadiazol-2- or -5-yl,1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, 3- or 4-pyridazinyl, pyrazinyl,1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-,3-, 4-, 5-, 6- or 7-indazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-,3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 2-, 4-, 5-, 6-, 7- or8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 3-, 5-, 6-, 7-or 8-quinoxalinyl, 1-, 4-, 5-, 6-, 7- or 8-phthalazinyl. Thecorresponding N-oxides of these compounds are furthermore included,i.e., for example, 1 -oxy-2-, -3- or -4-pyridyl.

[0209] The N-containing heterocycles pyrrolyl, imidazolyl, quinolyl,pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl areparticularly preferred. Pyridyl is either 2-, 3- or 4-pyridyl. Thienylis either 2- or 3-thienyl. Furyl is either 2- or 3-furyl.

[0210] Monosubstituted phenyl radicals can be substituted in the 2, 3 or4 position, disubstituted in the 2,3, 2,4, 2,5, 2,6, 3,4 or 3,5position, or trisubstituted in the 2,3,4, 2,3,5, 2,3,6, 2,4,5, 2,4,6 or3,4,5 position. The same correspondingly also applies analogously to theN-containing hetero-aromatics, the thiophene or the furyl radical.

[0211] If a radical is di- or trisubstituted, the substituents can beidentical or different.

[0212] If R(3) and R(4) are together a chain of 4 or 5 methylene groups,of which one methylene group can be replaced by —O—, —S—, —NH— etc.,then these radicals together with the nitrogen atom of the compound ofthe formula I form a 5- or 6-membered nitrogen heterocycle, such as, forexample, pyrrolidine, piperidine, morpholine, thiomorpholine etc.

[0213] If the compounds of the formula I contain one or more acidic orbasic groups or one or more basic heterocycles, the invention alsoincludes the corresponding physiologically or toxicologically tolerablesalts, in particular the pharmaceutically utilizable salts. Thus thecompounds of the formula I which carry acidic groups, e.g. one or moreCOOH groups, for example as alkali metal salts, preferably sodium orpotassium salts, or as alkaline earth metal salts, e.g. calcium ormagnesium salts, or as ammonium salts, e.g. as salts with ammonia ororganic amines or amino acids, can be used. Compounds of the formula Iwhich carry one or more basic, i.e. protonatable, groups or contain oneor more basic heterocyclic rings can also be used in the form of theirphysiologically tolerable acid addition salts with inorganic or organicacids, for example as hydrochlorides, phosphates, sulfates,methanesulfonates, acetates, lactates, maleates, fumarates, malates,gluconates etc. If the compounds of the formula I simultaneously containacidic and basic groups in the molecule, the invention also includesinternal salts, so-called betaines, in addition to the salt formsdescribed. Salts can be obtained from the compounds of the formula Iaccording to customary processes, for example by combination with anacid or base in a solvent or dispersant or alternatively from othersalts by anion exchange.

[0214] If they are appropriately substituted, the compounds of theformula I can be present in stereoisomeric forms. If the compounds ofthe formula I contain one or more asymmetric centers, theseindependently of one another can have the S configuration or the Rconfiguration. The invention includes all possible stereoisomers, e.g.enantiomers or diastereomers, and mixtures of two or more stereoisomericforms, e.g. enantiomers and/or diastereomers, in any desired ratios. Theinvention thus includes enantiomers, for example, in enantiomericallypure form, both as levo- and as dextrorotatory antipodes, and also inthe form of mixtures of the two enantiomers in different ratios or inthe form of racemates. If desired, the individual stereoisomers can beprepared by resolution of a mixture according to customary methods or,for example, by stereoselective synthesis. If mobile hydrogen atoms arepresent, the present invention also comprises all tautomeric forms ofthe compounds of the formula I.

[0215] The compounds of the formula I can be prepared by differentchemical processes, which are likewise included in the presentinvention. Some typical routes are outlined in the reaction sequencesdesignated below as schemes 1, 2, 3 and 4. The radicals R(1) to R(8)used here are in each case defined as indicated above, if not statedotherwise below.

[0216] Thus a compound of the formula I according to scheme 1 isobtained, for example, starting from diphenic anhydride derivatives ofthe formula II as precursors which are commercially obtainable or knownfrom the literature. Reduction of the compounds II using sodiumborohydride followed by reaction with potassium phthalimide as describedin Tetrahedron 45 (1989) 1365-1376 yields the biphenylcarboxylic acidsof the formula IV. By coupling with amines of the formula HNR(3)R(4)followed by hydrazinolysis of the phthalimide, the aminomethyl compoundsof the formula VI are obtained, from which, by reaction with suitablederivatives of the formula R(1)-X, the compounds of the formula Iaccording to the invention are obtained in which R(2) is hydrogen andR(1), R(3), R(4), R(5), R(6), R(7) and R(8) have the meanings indicatedabove. Subsequent alkylation using suitable alkylating agents of theformula R(2)Y, in which Y is a nucleofugic leaving group, e.g. Cl, Br orI, yields the corresponding compounds of the formula I in which R(2) isalkyl having 1 to 4 carbon atoms. Alternatively, the biphenylcarboxylicacids of the formula IV can also be converted by hydrazinolysis to theaminocarboxylic acids of the formula VII which are then converted byreaction of the amino group with compounds of the formulae R(1)-X andR(2)-Y followed by amidation of the carboxylic acids with amines of theformula HNR(3)R(4) to give compounds of the formula I according to theinvention (scheme 2).

[0217] In some cases, it can be useful to first prepare compounds of theformula la (scheme 3) in which R(9) is an easily removable radical, suchas, for example, tert-butyl or benzyl, by one of the previouslymentioned methods. After removal of the corresponding protective group,e.g. with trifluoroacetic acid for the Boc group or by catalytichydrogenation for the benzyloxy-carbonyl radical, the compounds of theformula IX are obtained, which can then in turn be converted into othercompounds of the formula I according to the invention by reaction withcompounds of the formula R(1)-X.

[0218] Another possibility for the preparation of compounds of theformula la consists in the palladium-catalyzed coupling of a phenylbromide or iodide of the formula X with a phenylboronic acid of theformula XI (Suzuki coupling; scheme 4), which can be carried out, forexample, in the presence of Pd[(PPh)₃]₄ as a catalyst, sodium carbonateas a base and 1,2-dimethoxyethane as a solvent. The compounds of theformula la can then be converted into other compounds of the formula Iaccording to the invention as described above and in scheme 3. Thenecessary boronic acids XI can be obtained from the compounds XII, inwhich Z represents hydrogen, bromine or iodine, by ortholithiationrespectively metal-halogen exchange and subsequent reaction with boricacid trimethylate.

[0219] The abovementioned reactions of the compounds of the formulae VI,VII and IX with compounds of the formula R(1)-X correspond to the knownconversion of an amine to a carboxamide, sulfonamide, carbamate, urea orthiourea derivative. The radical X here is a suitable nucleofugicleaving group, such as, for example, F, Cl, Br, imidazole, O-succinimideetc.

[0220] For the preparation of compounds of the formula I or VIII inwhich R(1) is C(O)OR(9), i.e. carbamates, compounds of the formulaR(1)-X, for example, are used in which X is chlorine or 0-succinimide,i.e. chloroformates or succinimidocarbonates.

[0221] For the preparation of compounds of the formula I or VIII inwhich R(1) is SO₂R(10), i.e. sulfonamides, as a rule compounds of theformula R(1)-X are used in which X is chlorine, i.e. sulfonyl chlorides.

[0222] For the preparation of compounds of the formula I or VIII inwhich R(1) is COR(11), i.e. carboxamides, compounds of the formulaR(1)-X, for example, are used in which X is chlorine, imidazole oracetoxy, i.e. carbonyl chlorides, carboxylic acid imidazolides or mixedanhydrides. However, the free acids of the formula R(1)-OH can also beused in the presence of suitable condensing agents such as carbodiimidesor uronium salts such as TOTU.

[0223] For the preparation of compounds of the formula I or VIII inwhich R(1) is CONR(12)R(13) or C(S)NR(12)R(13), i.e. ureas or thioureas,instead of the compounds of the formula R(1)-X it is also possible touse compounds of the formula R(12)N(═C═O), or R(12)N(═C═S), i.e.isocyanates or isothiocyanates.

[0224] The abovementioned reactions of the compounds of the formula IVor VIII with amines of the formula HNR(3)R(4) correspond to the knownconversion of a carboxylic acid to a carboxamide. Numerous methods havebeen described in the literature for carrying out these reactions. Theycan be carried out particularly advantageously by activation of thecarboxylic acid, e.g. with dicyclohexylcarbodiimide (DCC), ifappropriate with addition of hydroxybenzotriazole (HOBT) ordimethylaminopyridine (DMAP), or withO-[(cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyluroniumtetrafluoroborate (TOTU). However, reactive acid derivatives can also besynthesized first according to known methods, e.g. acid chlorides byreaction of the carboxylic acids of the formula IV or VIII withinorganic acid halides, such as, for example, SOCl₂, or acidimidazolides by reaction with carbonyldiimidazole, which are thenreacted with the amines of the formula HNR(3)R(4), if appropriate withthe addition of an auxiliary base.

[0225] In all procedures, it may be appropriate to temporarily protectfunctional groups in the molecule in certain reaction steps. Suchprotective group techniques are familiar to the person skilled in theart. The choice of a protective group for groups under consideration andthe processes for their introduction and removal are described in theliterature and can if necessary be adapted to the individual casewithout difficulties.

[0226] The compounds of the formula I according to the invention andtheir physiologically tolerable salts can thus be used in animals,preferably in mammals, and in particular in humans, as pharmaceuticalson their own, in mixtures with one another or in the form ofpharmaceutical preparations. The present invention also relates to thecompounds of the formula I and their physiologically tolerable salts foruse as pharmaceuticals, their use in the therapy and prophylaxis of thesyndromes mentioned and their use for the production of medicamentstherefor and of medicaments having K⁺ channel-blocking action. Thepresent invention furthermore relates to pharmaceutical preparationswhich, as active constituent, contain an efficacious dose of at leastone compound of the formula I and/or of a physiologically tolerable saltthereof in addition to customary, pharmaceutically innocuous vehiclesand excipients. The pharmaceutical preparations normally contain 0.1 to90% by weight of the compounds of the formula I and/or theirphysiologically tolerable salts. The pharmaceutical preparations can beprepared in a manner known per se. To this end, the compounds of theformula I and/or their physiologically tolerable salts are brought,together with one or more solid or liquid pharmaceutical vehicles and/orexcipients and, if desired, in combination with other pharmaceuticalactive compounds, into a suitable administration form or dose form,which can then be used as a pharmaceutical in human medicine orveterinary medicine.

[0227] Pharmaceuticals which contain compounds of the formula Iaccording to the invention and/or their physiologically tolerable saltscan be administered orally, parenterally, e.g. intravenously, rectally,by inhalation or topically, the preferred administration being dependenton the individual case, e.g. the particular form of the disease to betreated.

[0228] The person skilled in the art is familiar on the basis of his/herexpert knowledge with which excipients are suitable for the desiredpharmaceutical formulation. In addition to solvents, gel-forming agents,suppository bases, tablet excipients and other active compound carriers,it is possible to use, for example, antioxidants, dispersants,emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers,agents for achieving a depot effect, buffer substances or colorants. Forthe obtainment of an advantageous therapeutic action, the compounds ofthe formula I can also be combined with other pharmaceutical activecompounds. Thus in the treatment of cardiovascular diseases advantageouscombinations with substances having cardiovascular activity arepossible. Possible combination partners of this type which areadvantageous for cardiovascular disorders are, for example, otherantiarrhythmics, i.e. class I, class II or class III antiarrhythmics,such as, for example, IK_(s) or IK_(r) channel blockers, e.g.dofetilide, or furthermore hypotensive substances such as ACE inhibitors(for example enalapril, captopril, ramipril), angiotensin antagonists,K⁺ channel activators, and also alpha- and beta-receptor blockers, butalso sympathomimetic compounds and compounds having adrenergic activity,as well as Na⁺/H⁺ exchange inhibitors, calcium channel antagonists,phosphodiesterase inhibitors and other substances having a positiveinotropic action, such as, for example, digitalis glycosides, ordiuretics.

[0229] For an oral administration form, the active compounds are mixedwith the additives suitable therefor, such as vehicles, stabilizers orinert diluents, and brought by the customary methods into the suitableadministration forms, such as tablets, coated tablets, hard gelatincapsules, aqueous, alcoholic or oily solutions. Inert carriers which canbe used are, for example, gum arabic, magnesia, magnesium carbonate,potassium phosphate, lactose, glucose or starch, in particularcornstarch. In this case, preparation can be carried out both as dry andas moist granules. Suitable oily vehicles or solvents are, for example,vegetable or animal oils, such as sunflower oil or cod-liver oil.Suitable solvents for aqueous or alcoholic solutions are, for example,water, ethanol or sugar solutions or mixtures thereof. Furtherexcipients, also for other administration forms, are, for example,polyethylene glycols and polypropylene glycols.

[0230] For subcutaneous or intravenous administration, the activecompounds, if desired with the substances customary therefor such assolubilizers, emulsifiers or further excipients, are brought intosolution, suspension or emulsion. The compounds of the formula I andtheir physiologically tolerable salts can also be lyophilized and thelyophilizates obtained used, for example, for the production ofinjection or infusion preparations. Suitable solvents are, for example,water, physiological saline solution or alcohols, e.g. ethanol,propanol, glycerol, and in addition also sugar solutions such as glucoseor mannitol solutions, or alternatively mixtures of the various solventsmentioned.

[0231] Suitable pharmaceutical formulations for administration in theform of aerosols or sprays are, for example, solutions, suspensions oremulsions of the active compounds of the formula I or theirphysiologically tolerable salts in a pharmaceutically acceptablesolvent, such as, in particular, ethanol or water, or a mixture of suchsolvents. If required, the formulation can also contain otherpharmaceutical excipients such as surfactants, emulsifiers andstabilizers, and a propellant. Such a preparation contains the activecompound customarily in a concentration of approximately 0.1 to 10, inparticular of approximately 0.3 to 3, percent by weight.

[0232] The dose of the active compound of the formula I or of thephysiologically tolerable salts thereof to be administered depends onthe individual case and is to be adjusted to the conditions of theindividual case as customary for an optimum action. Thus it depends, ofcourse, on the frequency of administration and on the potency andduration of action of the compounds in each case employed for therapy orprophylaxis, but also on the nature and severity of the illness to betreated and on sex, age, weight and individual responsiveness of thehuman or animal to be treated and on whether treatment is acute orprophylactic. Customarily, the daily dose of a compound of the formula Ion administration to a patient weighing approximately 75 kg is 0.001mg/kg of body weight to 100 mg/kg of body weight, preferably 0.01 mg/kgof body weight to 20 mg/kg of body weight. The dose can be administeredin the form of an individual dose or can be divided into two or more,e.g. 2, 3 or 4, individual doses. In particular in the treatment ofacute cases of cardiac arrhythmias, for example in an intensive careunit, parenteral administration by injection or infusion, e.g. by anintravenous continuous infusion, can also be advantageous.

[0233] Experimental section

[0234] List of abbreviations

[0235] CDI Carbonyidiimidazole

[0236] DIC Diisopropylcarbodiimide

[0237] DMAP 4-Dimethylaminopyridine

[0238] DMF N,N-Dimethylformamide

[0239] EDAC N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0240] EA Ethyl acetate

[0241] m.p. Melting point (if not stated otherwise the melting points ofthe

[0242] unpurified crude products are stated; the melting points of therespective pure substances can definitely be markedly higher)

[0243] HOBT 1-Hydroxy-1H-benzotriazole

[0244] in vac. In vacuo

[0245] S Solvent

[0246] Me Methyl

[0247] RT Room temperature

[0248] THF Tetrahydrofuran

[0249] TOTUO-[(Cyano(ethoxycarbonyl)methylene)amino]-1,1,3,3-tetramethyl-uroniumtetrafluoroborate

[0250] Precursor 1: 7H-Dibenzo[c,e]oxepin-5-one

[0251] 9.0 g (0.24 mol) of sodium borohydride were added in portions at5° C. in the course of 10 min to a suspension of 50.0 g (0.22 mol) ofdiphenic anhydride in 220 ml of DMF. After stirring at RT for 1 h, thereaction mixture was poured onto 220 ml of 6 M hydrochloric acid,diluted with 750 ml of water and stirred for 2 h. The depositedprecipitate was filtered off with suction and 35.0 g of7H-dibenzo[c,e]oxepin-5-one were obtained;

[0252] m.p. 131° C.

[0253] Precursor 2: 2′-Phthalimidomethylbiphenyl-2-carboxylic Acid

[0254] A mixture of 35 g (0.17 mol) of 7H-dibenzo[c,e]oxepin-5-one and30.8 g (0.17 mol) of potassium phthalimide in 330 ml of DMF was heatedat 170° C. for 18 h. After cooling, the deposited precipitate wasfiltered off with suction and introduced into 160 ml of glacial aceticacid. After stirring for 1 h, the mixture was diluted with 650 ml of icewater and the deposited product was filtered off with suction and driedin vacuo. 44.8 g of 2′-phthalimidomethylbiphenyl-2-carboxylic acid wereobtained; m.p. 198° C.

[0255] Precursor 3: 2′-Aminomethylbiphenyl-2-carboxylic Acid

[0256] A suspension of 10.0 g (28 mmol) of2′-phthalimidomethylbiphenyl-2-carboxylic acid in 450 ml of methanol wastreated with 20 ml of hydrazine hydrate and heated at 40° C. for 1.5 h.The reaction mixture was concentrated and the residue was taken up in250 ml of methylene chloride. After filtering off undissolved2,3-dihydrophthalazine-1,4-dione, the mother liquor was concentrated and4.8 g of 2′-aminomethylbiphenyl-2-carboxylic acid were obtained.

[0257] General Procedure for the Synthesis of MixedSuccinimidocarbonates from Alcohols (precursors 4a-4k)

[0258] 5.0 g (19.5 mmol) of disuccinimidyl carbonate are added inportions at 0° C. to a solution of 19.5 mmol of the appropriate alcoholand 1.2 g (9.8 mmol) of DMAP in 30 ml of methylene chloride and 30 ml ofacetonitrile. After stirring at RT for 2.5 to 10 h, 25 ml of water areadded and the organic phase is washed a further 2 times with water.After drying and concentration, the corresponding succinimidocarbonatesare obtained, usually as crystalline solids.

[0259] Precursor 4a:

[0260] According to the general procedure, 3.2 g of 4-fluorobenzylN-succinimido-carbonate were obtained; m. p. 89° C. (ether).

[0261] Precursor4b:

[0262] From 11.7 mmol of 4-trifluoromethylbenzyl alcohol, correspondingto the general procedure 2.3 g of 4-trifluoromethylbenzylN-succinimido-carbonate were obtained; m.p. 102° C. (ether).

[0263] Precursor 4c:

[0264] From 10.5 mmol of α-methyl-4-(trifluoromethyl)benzyl alcohol,corresponding to the general procedure 1.6 g ofα-methyl-4-(trifluoromethyl)benzyl N-succinimidocarbonate were obtained;m.p. 115° C. (ether).

[0265] Precursor 4d:

[0266] From 19.5 mmol of 4,4,4-trifluorobutanol, corresponding to thegeneral procedure 4.0 g of 4,4,4-trifluorobutyl N-succinimidocarbonatewere obtained; m.p. 72° C. (ether).

[0267] Precursor 4e:

[0268] From 26.3 mmol of α-methyl-3-(trifluoromethyl)benzyl alcohol,corresponding to the general procedure 5.1 g ofα-methyl-3-(trifluoromethyl)benzyl N-succinimidocarbonate were obtained;m.p. 77° C. (ether).

[0269] Precursor 4f:

[0270] From 31.6 mmol of α-methyl-2,6-difluorobenzyl alcohol,corresponding to the general procedure 1.6 g ofα-methyl-2,6-difluorobenzyl N-succinimido-carbonate were obtained; m.p.108° C. (ether).

[0271] Precursor 4g:

[0272] From 25 mmol of α-methyl-2-(trifluoromethyl)benzyl alcohol,corresponding to the general procedure 3.5 g ofα-methyl-2-(trifluoromethyl)benzyl N-succinimidocarbonate were obtained.

[0273] Precursor4h:

[0274] From 25 mmol of (S)-1-phenylethanol, corresponding to the generalprocedure 3.5 g of (S)-α-methylbenzyl N-succinimidocarbonate wereobtained.

[0275] Precursor 4i:

[0276] From 25 mmol of (R)-1-phenylethanol, corresponding to the generalprocedure 3.5 g of (R)-α-methylbenzyl N-succinimidocarbonate wereobtained.

[0277] Precursor 4j:

[0278] From 25 mmol of α-methyl-4-fluorobenzyl alcohol, corresponding tothe general procedure 4.3 g of α-methyl-4-fluorobenzylN-succinimido-carbonate were obtained.

[0279] Precursor 4k:

[0280] From 9.8 mmol of (S)-1-phenyl-1-butanol, corresponding to thegeneral procedure 1.7 g of (S)-α-propylbenzyl N-succinimidocarbonatewere obtained.

[0281] Precursor 5a: 2′-Aminomethylbiphenyl-2-carboxylic acidphenethylamide

[0282] From 2′-phthalimidomethylbiphenyl-2-carboxylic acid (precursor2), after activation with CDI and reaction with phenethylamine,2′-phthalimido-methylbiphenyl-2-carboxylic acid phenethylamide wasobtained; m.p. 156° C.

[0283] 5.0 g (10.9 mmol) of the product were dissolved in 200 ml ofmethanol and treated with 5 ml of hydrazine hydrate. After stirring at40° C. for 1 h, the reaction mixture was concentrated and the residuewas taken up in methylene chloride. After filtering off the2,3-dihydrophthalazine-1,4-dione formed, the mother liquor wasconcentrated and the residue was purified by flash chromatography usingmethylene chloride/methanol 20:1. 3 g of2′-aminomethylbiphenyl-2-carboxylic acid phenethylamide were obtained.

[0284] Precursor 5b: 2′-Aminomethylbiphenyl-2-carboxylic acidbenzylamide

[0285] From 2′-phthalimidomethylbiphenyl-2-carboxylic acid (precursor2), after conversion into the acid chloride using thionyl chloride andreaction with benzylamine, 2′-phthalimidomethylbiphenyl-2-carboxylicacid benzylamide was obtained. 1.2 g (2.7 mmol) of the product weredissolved in 55 ml of methanol and treated with 1.35 ml of hydrazinehydrate. After stirring at 40° C. for 1 h, the reaction mixture wasconcentrated and the residue was taken up in methylene chloride. Afterfiltering off the 2,3-dihydro-phthalazine-1,4-dione formed, the motherliquor was concentrated and the residue was purified by flashchromatography using methylene chloride/methanol 30:1. 0.49 g of2′-aminomethylbiphenyl-2-carboxylic acid benzylamide was obtained.

[0286] Precursor 5c: 2′-Aminomethylbiphenyl-2-carboxylic acidisopentylamide

[0287] From 3 g (8.4 mmol) of 2′-phthalimidomethylbiphenyl-2-carboxylicacid (precursor 2), by reaction with isopentylamine in the presence ofHOBT and DIC, 3.2 g of 2′-phthalimidomethylbiphenyl-2-carboxylic acidisopentylamide were obtained; m.p. 169° C. The product was dissolved in100 ml of methanol and treated with 5 ml of hydrazine hydrate. Afterstirring at 40° C. for 1 h, the cooled reaction mixture was filtered.The filtrate was concentrated and the residue was taken up in methylenechloride. After washing with water, drying and concentrating, 1.8 g of2′-amino-methylbiphenyl-2-carboxylic acid isopentylamide were obtained.

[0288] Precursor 5d: 2′-Aminomethylbiphenyl-2-carboxylic acid2-(2-pyridyl)ethyl-amide

[0289] From 10 g (28 mmol) of 2′-phthalimidomethylbiphenyl-2-carboxylicacid (precursor 2), by reaction with 2-(2-pyridyl)ethylamine in thepresence of HOBT and DIC, 13 g of2′-phthalimidomethylbiphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamidewere obtained; m.p. 155° C. The product was suspended in 300 ml ofmethanol and treated with 20 ml of hydrazine hydrate. After stirring at40° C. for 1 h, the cooled reaction mixture was filtered. The filtratewas concentrated and the residue was taken up in EA. The product wasextracted into the aqueous phase 2 times using 2 M hydrochloric acid.The aqueous phase was then rendered alkaline with potassium carbonateand extracted 2 times with EA. After washing with water, drying andconcentrating, 7.3 g of 2′-aminomethylbiphenyl-2-carboxylic acid2-(2-pyridyl)ethylamide were obtained.

[0290] Precursor 6: 2′-(Benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid

[0291] 500 mg (2 mmol) of benzyl N-succinimidocarbonate dissolved in 2.5ml of dioxane were added dropwise at 0° C. to a solution of 455 mg (2mmol) of 2′-aminomethylbiphenyl-2-carboxylic acid (precursor 3) and 336mg (4 mmol) of sodium hydrogencarbonate in 5 ml of dioxane and 5 ml ofwater. After stirring at RT for 4 h, the mixture was concentrated invacuo, diluted with water, acidified and extracted with ethyl acetate.590 mg of 2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acidwere obtained.

[0292] Precursor 7:2′-(tert-Butoxycarbonylaminomethyl)biphenyl-2-carboxylic acid

[0293] 65 ml of 1 M sodium hydroxide solution were added to a solutionof 12.0 g (53 mmol) of 2′-aminomethylbiphenyl-2-carboxylic acid(precursor 3) in 130 ml of 1,4-dioxane and 65 ml of water and, aftercomplete dissolution, 12.6 g (58 mmol) of di-tert-butyl dicarbonate wereadded. After stirring at RT for 2 h, the mixture was concentrated invacuo, diluted with water and extracted 2 times with methylene chloride.The aqueous phase was acidified with 1 M potassium hydrogensulfatesolution and extracted with ethyl acetate. After extensiveconcentration, addition of n-heptane and allowing to stand overnight,the product precipitated and 7.6 g of2′-(tert-butoxycarbonylaminomethyl)biphenyl-2-carboxylic acid wereobtained;

[0294] m.p. 136° C.

[0295] General Procedure for the Removal of the Boc Protective Group:

[0296] The n-Boc-protected aminomethylbiphenyl derivative (1 g to 10 mlof solution) was added to a solution of trifluoroacetic acid indichloromethane (30% strength). The mixture was stirred at roomtemperature for 30 minutes and the solvent was then removed in vacuo ona rotary evaporator. The residue was taken up in ethyl acetate andwashed with saturated sodium hydrogencarbonate solution. The organicphase was dried over magnesium sulfate, the solvent was removed in vacuoand the corresponding 2′-aminomethylbiphenyl-2-carboxamides wereobtained.

[0297] Precursor 8a: 2′-Aminomethylbiphenyl-2-carboxylic acid(2,4-difluoro-benzyl)amide

[0298] The compound was obtained from the Boc-protected compound(Example 8c) according to the general procedure. Alternatively, thecompound can also be isolated directly as the trifluoroacetate andreacted further.

[0299] Further Precursors 8:

[0300] The corresponding amines were analogously liberated from theBoc-protected compounds of Examples 8d-8o and 10a-10o.

[0301] General Procedure for the Reaction of Aminomethylbiphenyls withSuccinimidocarbonates to Give Carbamates (Examples 1a to 1u)

[0302] 0.45 mmol of the respective succinimidocarbonate dissolved in 2ml of dioxane is slowly added dropwise to a solution of 0.45 mmol of therespective 2′-aminomethylbiphenyl and 38 mg (0.45 mmol) of sodiumhydrogencarbonate in 2 ml of dioxane and 2 ml of water. The mixture isstirred at RT for 2 to 12 h, concentrated, diluted with water andextracted with EA, and the organic phase is washed with water. Afterdrying and concentration, the corresponding carbamates are obtained.

EXAMPLE 1a2′-(4-Trifluoromethylbenzyloxycarbonylaminomethyl)bi-phenyl-2-carboxylicacid phenethylamide

[0303]

[0304] From 0.45 mmol of 2′-aminomethylbiphenyl-2-carboxylic acidphenethyl-amide and 4-trifluoromethylbenzyl N succinimidocarbonate(precursor 4b), according to the general working procedure 226 mg of2′-(4-trifluoro-methylbenzyloxycarbonylaminomethyl)biphenyl-2-carboxylicacid phenethylamide were obtained. MS (ES+): m/e=533 (M+1).

EXAMPLE 1b 2′-(Benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acidphenethylamide

[0305]

[0306] From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acidphenethylamide and benzyl N-succinimidocarbonate, according to thegeneral working procedure 66 mg of2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acidphenethylamide were obtained as an oil. MS (ES+): m/e=456 (M+1).

EXAMPLE 1c2′-(Methylsulfonylethyloxycarbonylaminomethyl)biphenyl-2-carboxylic acidphenethylamide

[0307]

[0308] From 0.45 mmol of 2′-aminomethylbiphenyl-2-carboxylic acidphenethyl-amide (precursor 5a) and methylsulfonylethylN-succinimidocarbonate, according to the general working procedure 164mg of2′-(methylsulfonylethyloxycarbonylaminomethyl)biphenyl-2-carboxylic acidphenethylamide were obtained as an oil. MS (ES+): m/e=481 (M+1).

EXAMPLE 1d2′-(4-Trifluoromethylbenzyloxycarbonylaminomethyl)biphenyl-2-carboxylicacid 2-(2-pyridyl)ethylamide

[0309]

[0310] From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid2-(2-pyridyl)-ethylamide (precursor 5d) and 4-trifluoromethylbenzylN-succinimido-carbonate (precursor 4b), according to the general workingprocedure 170 mg of2′-(4-trifluoromethylbenzyloxycarbonylaminomethyl)biphenyl-2-carboxylicacid 2-(2-pyridyl)ethylamide were obtained. MS (ES+): m/e=534 (M+1).

EXAMPLE 1e2′-(4-Fluorobenzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid2-(2-pyridyl)ethylamide

[0311]

[0312] From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid2-(2-pyridyl)-ethylamide (precursor 5d) and 4-fluorobenzylN-succinimidocarbonate (precursor 4a), according to the general workingprocedure 150 mg of2′-(4-fluorobenzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid2-(2-pyridyl)ethylamide were obtained. MS (ES+): m/e=484 (M+1).

EXAMPLE 1f(±)-2′-(α-Methyl-4-(trifluoromethyl)benzyloxycarbonylamino-methyl)biphenyl-2-carboxylicacid 2-(2-pyridyl)ethylamide

[0313]

[0314] From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid2-(2-pyridyl)-ethylamide (precursor 5d) andα-methyl-4-(trifluoromethyl)benzyl N-succinimidocarbonate (precursor4c), according to the general working procedure 170 mg of2′-(α-methyl-4-(trifluoromethyl)benzyloxycarbonyl-aminomethyl)biphenyl-2-carboxylicacid 2-(2-pyridyl)ethylamide were obtained as a racemate. MS (ES+):m/e=548 (M+1).

EXAMPLE 1g(S)-2′-(α-Methyl-4-(trifluoromethyl)benzyloxycarbonylamino-methyl)biphenyl-2-carboxylicacid 2-(2-pyridyl)ethylamide

[0315]

[0316] The S enantiomer was obtained from the corresponding racemate(Example 1f) by preparative HPLC on a Chiralpak AD 250×4.6 column usingn-hexane/ethanol/isopropanol (10:1:1, 0.3% each of trifluoroaceticacid/diethylamine) as solvent.

EXAMPLE 1h(R)-2′-(α-Methyl-4-(trifluoromethyl)benzyloxycarbonylamino-methyl)biphenyl-2-carboxylicacid 2-(2-pyridyl)ethylamide

[0317]

[0318] The R enantiomer was obtained from the corresponding racemate(Example 1f) by preparative HPLC on a Chiralpak AD 250×4.6 column usingn-hexane/ethanol/isopropanol (10:1:1, 0.3% each of trifluoroaceticacid/diethylamine) as solvent.

EXAMPLE 1i2′-(4,4,4-Trifluorobutyloxycarbonylaminomethyl)biphenyl-2-carboxylicacid 2-(2-pyridyl)ethylamide

[0319]

[0320] From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid2-(2-pyridyl)-ethylamide (precursor 5d) and 4,4,4-trifluorobutylN-succinimidocarbonate (precursor 4d), according to the general workingprocedure 140 mg of 2′(4,4,4-trifluorobutyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid2-(2-pyridyl)ethylamide were obtained. MS (ES+): m/e=486 (M+1).

EXAMPLE 1j(S)-2′-(α-Methylbenzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid2-(2-pyridyl)-ethylamide

[0321]

[0322] From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid2-(2-pyridyl)-ethylamide (precursor 5d) and (S)-α-methylbenzylN-succinimido-carbonate (precursor 4h), according to the general workingprocedure 60 mg of(S)-2′-(α-methylbenzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid2-(2-pyridyl)ethylamide were obtained. MS (ES+): m/e=480 (M+1).

EXAMPLE 1k(R)-2′-(α-Methylbenzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid2-(2-pyridyl)ethylamide

[0323]

[0324] From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid2-(2-pyridyl)-ethylamide (precursor 5d) and (R)-α-methylbenzylN-succinimido-carbonate (precursor 4i), according to the general workingprocedure 60 mg of(R)-2′-(α-methylbenzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid2-(2-pyridyl)ethylamide were obtained. MS (ES+): m/e=480 (M+1).

EXAMPLES 1l-1u

[0325] The following compounds were obtained from the respectiveprecursors according to the general working procedure and analogously toExamples 1a-1k: Example Pre- MS (ES+): No. cursors Structure m/e = 1l 5d+4g

548 1m 5d +4e

548 1n 5d +4f

516 1o 8a +4i

501 1p 8a +4c

569 1q 8a +4k

529 1r 5d +4k

508 1s 8a +4a

505 (m.p. 104° C.) 1t 8a +4d

507 (m.p. 111° C.) 1u

452

[0326] General Procedure for the Reaction of Aminomethylbiphenyls withChloroformic Acid Esters to Give Carbamates (Examples 2a to 2m):

[0327] 0.32 mmol of the respective chloroformic acid ester dissolved in1 ml of methylene chloride is slowly added dropwise at 5° C. to asolution of 0.3 mmol of the respective 2′-aminomethylbiphenyl and 37 mg(0.36 mmol) of triethylamine in 6 ml of methylene chloride. The mixtureis stirred at RT overnight, poured onto water and the organic phase iswashed once more with water. After concentration, the residue ispurified by flash chromatography.

EXAMPLE 2a 2′-(Butoxycarbonylaminomethyl)biphenyl-2-carboxylic acid2-(2-pyridyl)ethylamide

[0328]

[0329] From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid2-(2-pyridyl)-ethylamide (precursor 5d) and butyl chloroformate,according to the general working procedure 69 mg of2′-(butoxycarbonylaminomethyl)-biphenyl-2-carboxylic acid2-(2-pyridyl)ethylamide were obtained as an oil.

[0330] MS (ES+): m/e=432 (M+1).

EXAMPLE 2b 2′-(Benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid(3-methylbutyl)amide

[0331]

[0332] From 0.27 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid(3-methyl-butyl)amide (precursor 5c) and benzyl chloroformate, accordingto the general working procedure 44 mg of2′-(benzyloxycarbonylaminomethyl)-biphenyl-2-carboxylic acid(3-methylbutyl)amide were obtained;

[0333] m.p. 112° C. MS (ES+): m/e=431 (M+1).

EXAMPLE 2c 2′-(Benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid2-(2-pyridyl)ethylamide

[0334]

[0335] From 0.24 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid2-(2-pyridyl)-ethylamide (precursor 5d) and benzyl chloroformate,according to the general working procedure 59 mg of2′-(benzyloxycarbonylaminomethyl)-biphenyl-2-carboxylic acid2-(2-pyridyl)ethylamide were obtained; m.p. 140° C. (heptane/EA). MS(ES+): m/e=466 (M+1).

EXAMPLE 2d 2′-(Butoxycarbonylaminomethyl)biphenyl-2-carboxylic acid(3-methylbutyl)amide

[0336]

[0337] From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid(3-methyl-butyl)amide (precursor 5c) and butyl chloroformate, accordingto the general working procedure 66 mg of2′-(butoxycarbonylaminomethyl)-biphenyl-2-carboxylic acid(3-methylbutyl)amide were obtained as a resin.

[0338] MS (ES+): m/e=397 (M+1).

EXAMPLE 2e2′-(2-Chlorobenzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid(3-methylbutyl)amide

[0339]

[0340] From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid(3-methylbutyl)amide (precursor 5c) and 2-chlorobenzyl chloroformate,according to the general working procedure 75 mg of2′-(2-chlorobenzyl-oxycarbonylaminomethyl)biphenyl-2-carboxylic acid(3-methylbutyl)amide were obtained as a resin. MS (ES+): m/e=465 (M+1).

EXAMPLE 2f 2′-(Methoxycarbonylaminomethyl)biphenyl-2-carboxylic acid(3-methylbutyl)amide

[0341]

[0342] From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid(3-methyl-butyl)amide (precursor 5c) and methyl chloroformate, accordingto the general working procedure followed by extraction with EA andpurification by flash chromatography 29 mg of2′-(methoxycarbonylaminomethyl)-biphenyl-2-carboxylic acid(3-methylbutyl)amide were obtained as a resin.

[0343] MS (ES+): m/e=355 (M+1).

EXAMPLE 2g 2′-(Phenoxycarbonylaminomethyl)biphenyl-2-carboxylic acid(3-methylbutyl)amide

[0344]

[0345] From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid(3-methyl-butyl)amide (precursor 5c) and phenyl chloroformate, accordingto the general working procedure followed by extraction with EA andpurification by flash chromatography 55 mg of2′-(phenoxycarbonylaminomethyl)-biphenyl-2-carboxylic acid(3-methylbutyl)amide were obtained as a resin.

[0346] MS (ES+): m/e=417 (M+1).

EXAMPLE 2h2′-(4-Carbomethoxyphenoxycarbonylaminomethyl)biphenyl-2-carboxylic acid3-methylbutyl)amide

[0347]

[0348] From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid(3-methyl-butyl)amide (precursor 5c) and (4-carbomethoxy)-phenylchloroformate, according to the general working procedure followed byextraction with EA and purification by flash chromatography 77 mg of2′-(4-carbomethoxy-phenoxycarbonylaminomethyl)biphenyl-2-carboxylic acid(3-methylbutyl)-amide were obtained as a resin. MS (ES+): m/e=475 (M+1).

EXAMPLE 2i2′-(2,2-Dimethylpropoxycarbonylaminomethyl)biphenyl-2-carboxylic acidphenethylamide

[0349]

[0350] From 0.45 mmol of 2′-aminomethylbiphenyl-2-carboxylic acidphenethylamide (precursor 5a) and neopentyl chloroformate, according tothe general working procedure followed by extraction with EA andpurification by flash chromatography 156 mg of2′-(2,2-dimethylpropoxycarbonyl-aminomethyl)biphenyl-2-carboxylic acidphenethylamide were obtained. MS (ES+): m/e=445 (M+1).

EXAMPLES 2j-2m

[0351] The following compounds were obtained analogously to Examples2a-2i: Example MS (ES+): No. Structure m/e = M.p. 2j

491 2k

473 107 2l

503 123 2m

482

[0352] General Procedure for the Reaction of Aminomethylbiphenyls withSulfonyl Chlorides to Give Sulfonamides (Examples 3a to 3t):

[0353] 0.66 mmol of the respective sulfonyl chloride is slowly addeddropwise at 0° C. to a solution of 0.61 mmol of the respective2′-aminomethylbiphenyl and 74 mg (0.73 mmol) of triethylamine in 5 ml ofmethylene chloride. After stirring at RT for 12 h, the reaction mixtureis concentrated in vacuo, the residue is stirred with 25 ml of water for2 h and the crystallized product is filtered off with suction.

EXAMPLE 3a2′-(3-Trifluoromethylphenylsulfonylaminomethyl)biphenyl-2-carboxylicacid phenethylamide

[0354]

[0355] From 0.61 mmol of 2′-aminomethylbiphenyl-2-carboxylic acidphenethylamide (precursor 5a) and 3-trifluoromethylphenylsulfonylchloride, according to the general working procedure 272 mg of2′-(3-trifluoromethyl-phenylsulfonylaminomethyl)biphenyl-2-carboxylicacid phenethylamide were obtained; m.p. 145° C. MS (ES+): m/e=539 (M+1).

EXAMPLE 3b 2′-(4-Acetylphenylsulfonylaminomethyl)biphenyl-2-carboxylicacid phenethylamide

[0356]

[0357] From 0.61 mmol of 2′-aminomethylbiphenyl-2-carboxylic acidphenethylamide (precursor 5a) and 4-acetylphenylsulfonyl chloride,according to the general working procedure 258 mg of2′-(4-acetylphenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acidphenethylamide were obtained;

[0358] m.p. 145° C. MS (ES+): m/e=513 (M+1).

EXAMPLE 3c 2′-(3-Nitrophenylsulfonylaminomethyl)biphenyl-2-carboxylicacid phenethylamide

[0359]

[0360] From 0.61 mmol of 2′-aminomethylbiphenyl-2-carboxylic acidphenethyl-amide (precursor 5a) and 3-nitrophenylsulfonyl chloride,according to the general working procedure 272 mg of2′-(3-nitrophenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acidphenethylamide were obtained; m. p. 145° C. MS (ES+): m/e=516 (M+1).

EXAMPLE 3d 2′-(Phenylsulfonylaminomethyl)biphenyl-2-carboxylic acidphenethylamide

[0361]

[0362] From 0.61 mmol of 2′-aminomethylbiphenyl-2-carboxylic acidphenethylamide (precursor 5a) and phenylsulfonyl chloride according tothe general working procedure 224 mg of2′-(phenylsulfonylaminomethyl)-biphenyl-2-carboxylic acid phenethylamidewere obtained; m. p.154° C. MS (ES+): m/e=471 (M+1).

EXAMPLE 3e 2′-(3-Fluorophenylsulfonylaminomethyl)biphenyl-2-carboxylicacid phenethylamide

[0363]

[0364] From 0.61 mmol of 2′-aminomethylbiphenyl-2-carboxylic acidphenethylamide (precursor 5a) and 3-fluorophenylsulfonyl chloride,according to the general working procedure 221 mg of2′-(3-fluorophenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acidphenethylamide were obtained;

[0365] m.p. 153° C. MS (ES+): m/e=489 (M+1).

EXAMPLE 3f 2′-(4-Ethylphenylsulfonylaminomethyl)biphenyl-2-carboxylicacid phenethylamide

[0366]

[0367] From 0.61 mmol of 2′-aminomethylbiphenyl-2-carboxylic acidphenethylamide (precursor 5a) and 4-ethylphenylsulfonyl chloride,according to the general working procedure 250 mg of2′-(4-ethylphenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acidphenethylamide were obtained;

[0368] m.p. 163° C. MS (ES+): m/e=499 (M+1).

EXAMPLE 3g2′-(3-Trifluoromethylphenylsulfonylaminomethyl)biphenyl-2-carboxylicacid benzylamide

[0369]

[0370] From 0.28 mmol of 2′-aminomethylbiphenyl-2-carboxylic acidbenzylamide (precursor5b) and 3-trifluoromethylphenylsulfonyl chloride,according to the general working procedure 131 mg of2′-(3-trifluoromethylphenyl-sulfonylaminomethyl)biphenyl-2-carboxylicacid benzylamide were obtained; m.p. 126° C. MS (ES+): m/e=525 (M+1).

EXAMPLE 3h 2′-(3-Acetylphenylsulfonylaminomethyl)biphenyl-2-carboxylicacid benzylamide

[0371]

[0372] From 0.28 mmol of 2′-aminomethylbiphenyl-2-carboxylic acidbenzylamide (precursor 5b) and 3-acetylphenylsulfonyl chloride,according to the general working procedure 110 mg of2′-(3-acetylphenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acidbenzylamide were obtained;

[0373] m.p. 182° C. MS (ES+): m/e=499 (M+1).

EXAMPLE 3i 2′-(3-Nitrophenylsulfonylaminomethyl)biphenyl-2-carboxylicacid benzylamide

[0374]

[0375] From 0.28 mmol of 2′-aminomethylbiphenyl-2-carboxylic acidbenzylamide (precursor 5b) and 3-nitrophenylsulfonyl chloride, accordingto the general working procedure 115 mg of2′-(3-nitrophenylsulfonylaminomethyl)-biphenyl-2-carboxylic acidbenzylamide were obtained; m.p. 175° C. MS (ES+): m/e=502 (M+1).

EXAMPLE 3j 2′-(3-Phenylsulfonylaminomethyl)biphenyl-2-carboxylic acidbenzylamide

[0376]

[0377] From 0.28 mmol of 2′-aminomethylbiphenyl-2-carboxylic acidbenzylamide (precursor 5b) and phenylsulfonyl chloride, according to thegeneral working procedure 95 mg of2′-(phenylsulfonylaminomethyl)biphenyl-2-carboxylic acid benzylamidewere obtained; m.p. 162° C. MS (ES+): m/e=457 (M+1).

EXAMPLE 3k 2′-(3-Fluorophenylsulfonylaminomethyl)biphenyl-2-carboxylicacid benzylamide

[0378]

[0379] From 0.28 mmol of 2′-aminomethylbiphenyl-2-carboxylic acidbenzylamide (precursor 5b) and 3-fluorophenylsulfonyl chloride,according to the general working procedure 112 mg of2′-(3-fluorophenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acidbenzylamide were obtained;

[0380] m.p. 147° C. MS (ES+): m/e=475 (M+1).

EXAMPLE 3l 2′-(Phenylsulfonylaminomethyl)biphenyl-2-carboxylic acid(3-methylbutyl)amide

[0381]

[0382] From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid(3-methyl-butyl)amide (precursor 5c) and phenylsulfonyl chloride,according to the general working procedure 100 mg of2′-(phenylsulfonylaminomethyl)-biphenyl-2-carboxylic acid(3-methylbutyl)amide were obtained;

[0383] m.p. 127° C. MS (ES+): m/e=437 (M+1).

EXAMPLE 3m 2′-(4-Fluorophenylsulfonylaminomethyl)biphenyl-2-carboxylicacid (3-methylbutyl)amide

[0384]

[0385] From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid(3-methyl-butyl)amide (precursor 5c) and 4-fluorophenylsulfonylchloride, according to the general working procedure 122 mg of2′-(4-fluorophenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acid(3-methylbutyl)amide were obtained; m.p. 149° C. MS (ES+): m/e=455(M+1).

EXAMPLE 3n 2′-(3-Fluorophenylsulfonylaminomethyl)biphenyl-2-carboxylicacid (3-methylbutyl)amide

[0386]

[0387] From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid(3-methyl-butyl)amide (precursor 5c) and 3-fluorophenylsulfonylchloride, according to the general working procedure 118 mg of2′-(3-fluorophenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acid(3-methylbutyl)amide were obtained; m.p. 141° C. MS (ES+): m/e=455(M+1).

EXAMPLE 3o 2′-(Isopropylsulfonylaminomethyl)biphenyl-2-carboxylic acid(3-methylbutyl)amide

[0388]

[0389] From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid(3-methyl-butyl)amide (precursor 5c) and isopropylsulfonyl chloride,according to the general working procedure followed by purification byflash chromatography 16 mg of2′-(isopropylsulfonylaminomethyl)biphenyl-2-carboxylic acid(3-methylbutyl)amide were obtained as an oil. MS (ES+): m/e=403 (M+1).

EXAMPLE 3p 2′-(Phenylsulfonylaminomethyl)biphenyl-2-carboxylic acid2-(2-pyridyl)ethylamide

[0390]

[0391] From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid2-(2-pyridyl)-ethylamide (precursor 5d) and phenylsulfonyl chloride,according to the general working procedure 117 mg of2′-(phenylsulfonylaminomethyl)-biphenyl-2-carboxylic acid2-(2-pyridyl)ethylamide were obtained;

[0392] m.p. 131° C. MS (ES+): m/e=472 (M+1).

EXAMPLE 3q 2′-(4-Fluorophenylsulfonylaminomethyl)biphenyl-2-carboxylicacid 2-(2-pyridyl)ethylamide

[0393]

[0394] From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid2-(2-pyridyl)-ethylamide (precursor 5d) and 4-fluorophenylsulfonylchloride, according to the general working procedure 106 mg of2′-(4-fluorophenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acid2-(2-pyridyl)ethylamide were obtained; m.p. 130° C. MS (ES+): m/e=490(M+1).

EXAMPLE 3r 2′-(3-Fluorophenylsulfonylaminomethyl)biphenyl-2-carboxylicacid 2-(2-pyridyl)ethylamide

[0395]

[0396] From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid2-(2-pyridyl)-ethylamide (precursor 5d) and 3-fluorophenylsulfonylchloride, according to the general working procedure 102 mg of2′-(3-fluorophenylsulfonyl-aminomethyl)biphenyl-2-carboxylic acid2-(2-pyridyl)ethylamide were obtained; m.p. 123° C. MS (ES+): m/e=490(M+1).

EXAMPLE 3s 2′-(Isopropylsulfonylaminomethyl)biphenyl-2-carboxylic acid2-(2-pyridyl)ethylamide

[0397]

[0398] From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid2-(2-pyridyl)-ethylamide (precursor 5d) and isopropylsulfonyl chloride,according to the general working procedure and subsequent extractionwith EA 40 mg of 2′-(isopropylsulfonylaminomethyl)biphenyl-2-carboxylicacid 2-(2-pyridyl)-ethylamide were obtained as an oil. MS (ES+): m/e=438(M+1).

[0399] The following compound was obtained analogously to Examples3a-3s: Example MS (ES+): No. Structure m/e = 3t

539

[0400] General Procedure for the Reaction of Aminomethylbiphenyls withCarbonyl Chlorides to Give Carboxamides (Examples 4a to 4l):

[0401] 0.36 mmol of the respective sulfonyl chloride is slowly addeddropwise at 0° C. to a solution of 0.34 mmol of the respective2′-aminomethylbiphenyl and 41 mg (0.41 mmol) of triethylamine in 5 ml ofmethylene chloride. After stirring at RT for 3 h, the reaction mixtureis concentrated in vacuo, the residue is stirred with 25 ml of water andthe precipitated product is filtered off with suction or isolated byextraction with EA.

EXAMPLE 4a 2′-(Benzoylaminomethyl)biphenyl-2-carboxylic acid(3-methylbutyl)amide

[0402]

[0403] From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid(3-methyl-butyl)amide (precursor 5c) and benzoyl chloride, according tothe general working procedure 75 mg of2′-(benzoylaminomethyl)biphenyl-2-carboxylic acid (3-methylbutyl)amidewere obtained; m.p. 147° C. MS (ES+): m/e=401 (M+1).

EXAMPLE 4b 2′-(Benzoylaminomethyl)biphenyl-2-carboxylic acid2-(2-pyridyl)ethylamide

[0404]

[0405] From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid2-(2-pyridyl)-ethylamide (precursor 5d) and benzoyl chloride, accordingto the general working procedure 98 mg of2′-(benzoylaminomethyl)biphenyl-2-carboxylic acid2-(2-pyridyl)ethylamide were obtained; m.p. 135° C. MS (ES+): m/e=436(M+1).

EXAMPLE 4c2′-{[2-(4-Methoxyphenyl)acetylamino]methyl}biphenyl-2-carboxylic acid2,4-difluorobenzylamide

[0406]

[0407] From 0.5 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid(2,4-di-fluorobenzyl)amide (precursor 8a) and 4-methoxyphenylacetylchloride, according to the general working procedure 160 mg of2′-{[2-(4-methoxy-phenyl)acetylamino]methyl}biphenyl-2-carboxylic acid2,4-difluoro-benzylamide were obtained; m.p. 138° C. MS (ES+): m/e=501(M+1).

[0408] The following compounds were obtained analogously to Examples4a-4c: Example ME (ES+) No. Structure m/e = M.p. 4d

480 4e

466 4f

466 4g

481 4h

465 4i

480 116° C. 4j

480 4k

508 4l

478

[0409] General Procedure for the Reaction of Aminomethylbiphenyls withIsocyanates to Give Ureas (Examples 5a-5e):

[0410] 0.36 mmol of the respective isocyanate dissolved in 0.5 ml ofmethylene chloride is slowly added dropwise at 0° C. to a solution of0.34 mmol of the respective 2′-aminomethylbiphenyl and 41 mg (0.41 mmol)of triethylamine in 5 ml of methylene chloride. After stirring at RT for3 h, the reaction mixture is concentrated in vacuo, the residue isstirred with 25 ml of water and the precipitated product is filtered offwith suction or isolated by extraction with EA.

EXAMPLE 5a 2′-[(3-Phenylureido)methyl]biphenyl-2-carboxylic acid(3-methylbutyl)amide

[0411]

[0412] From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid(3-methyl-butyl)amide (precursor 5c) and phenyl isocyanate, according tothe general working procedure 85 mg of2′-[(3-phenylureido)methyl]biphenyl-2-carboxylic acid(3-methylbutyl)amide were obtained; m.p. 194° C. MS (ES+): m/e=416(M+1).

EXAMPLE 5b 2′-[(3-Phenylureido)methyl]biphenyl-2-carboxylic acid2-(2-pyridyl)ethylamide

[0413]

[0414] From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid2-(2-pyridyl)-ethylamide (precursor 5d) and phenyl isocyanate, accordingto the general working procedure 101 mg of2′-[(3-phenylureido)methyl]biphenyl-2-carboxylic acid2-(2-pyridyl)ethylamide were obtained; m.p. 99° C. MS (ES+): m/e=451(M+1).

EXAMPLES 5c-5e

[0415] The following compounds were obtained analogously from2′-amino-methylbiphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide(precursor 5d) and the corresponding isocyanates: Example MS (ES+): No.Structure m/e = 5c

465 5d

479 5e

479

[0416] General Procedure for the Reaction of Biphenylcarboxylic Acidswith Amines to Give Amides (Examples 6a-6h):

[0417] 0.3 mmol of the respective amine is added dropwise at 0° C. to asolution of 0.28 mmol of the appropriate biphenylcarboxylic acid, 0.3mmol of HOBT and 0.3 mmol of DIC in 5 ml of THF and it is stirred at RTfor 12 h. The reaction mixture is diluted with EA and washed with dilutehydrochloric acid and sodium bicarbonate solution. After drying overmagnesium sulfate and concentrating in vacuo, the corresponding amide isobtained.

EXAMPLE 6a 2′-(Benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acidbenzylmethylamide

[0418]

[0419] From 0.28 mmol of2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid (precursor6) and benzylmethylamine, according to the general working procedure 89mg of 2′-(benzyloxycarbonylaminomethyl)-biphenyl-2-carboxylic acidbenzylmethylamide were obtained. MS (ES+): m/e=465 (M+1).

EXAMPLE 6b 2′-(Benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acidCcclohexylamide

[0420]

[0421] From 0.28 mmol of2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid (precursor6) and cyclohexylamine, according to the general working procedure 99 mgof 2′-(benzyloxycarbonylaminomethyl)-biphenyl-2-carboxylic acidcyclohexylamide were obtained. MS (ES+): m/e=443 (M+1).

EXAMPLE 6c 2′-(Benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acidphenylamide

[0422]

[0423] From 0.28 mmol of2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid (precursor6) and aniline, according to the general working procedure 66 mg of2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid phenylamidewere obtained. MS (ES+): m/e=437 (M+1).

EXAMPLE 6d 2′-(Benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid{N-methyl-N-[2-(2-pyridyl)ethyl]}amide

[0424]

[0425] From 0.28 mmol of2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid (precursor6) and 2-[2-(methylaminoethyl)]pyridine, according to the generalworking procedure and subsequent purification by flash chromatography 54mg of 2′-(benzyloxycarbonylaminomethyl)-biphenyl-2-carboxylic acid{N-methyl-N-[2-(2-pyridyl)ethyl]}amide were obtained. MS (ES+): m/e=480(M+1).

EXAMPLE 6e 2′-(Benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic aciddibutylamide

[0426]

[0427] From 0.28 mmol of2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid (precursor6) and dibutylamine, according to the general working procedure andsubsequent purification by flash chromatography 82 mg of2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid dibutylamidewere obtained. MS (ES+): m/e=473 (M+1).

EXAMPLE 6f 2′-(Benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid2-(2-pyridyl)ethylamide

[0428]

[0429] From 0.28 mmol of2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid (precursor6) and 2-(2-pyridyl)ethylamine, according to the general workingprocedure and subsequent purification by flash chromatography 85 mg of2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid2-(2-pyridyl)ethylamide were obtained; m.p. 140° C. (heptane/EA); MS(ES+): m/e=466 (M+1).

EXAMPLE 6g 2′-(Benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid(2,4-difluorobenzyl)amide

[0430]

[0431] From 0.28 mmol of2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid (precursor6) and 2,4-difluorobenzylamine, according to the general workingprocedure and subsequent purification by flash chromatography 99 mg of2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid(2,4-difluorobenzyl)amide were obtained. MS (ES+): m/e=487 (M+1).

EXAMPLE 6h 2′-(Benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid(2,2,2-trifluoroethyl)amide

[0432]

[0433] From 0.28 mmol of2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid (precursor6) and 2,2,2-trifluoroethylamine, according to the general workingprocedure and subsequent purification by flash chromatography 19 mg of2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid(2,2,2-trifluoroethyl)amide were obtained. MS (ES+): m/e=443 (M+1).

EXAMPLE 7a 2′-(Benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid2-[2-(1 -oxypyridyl)]ethylamide

[0434]

[0435] 47 mg of m-chloroperbenzoic acid dissolved in 2 ml of methylenechloride were added dropwise at 0° C. to a solution of 85 mg (0.18 mmol)of 2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid2-(2-pyridyl)-ethylamide (Example 6f) in 13 ml of methylene chloride andthe reaction mixture was stirred at RT for 12 h. The organic phase waswashed 2 times with sodium bicarbonate solution, dried over magnesiumsulfate and concentrated in vacuo. 79 mg of2′-(benzyloxycarbonylaminomethyl)-biphenyl-2-carboxylic acid2-[2-(1-oxypyridyl)]ethylamide were obtained.

[0436] MS (ES+): m/e=482 (M+1).

[0437] The following compounds were obtained from the correspondingpyridines analogously to Example 7a: Example MS (ES+): No. Structure m/e= 7b

482 7c

496

[0438] General Procedure for the Reaction of Biphenylcarboxylic Acidswith Amines to give Amides (Examples 8a-8c):

[0439] 0.44 mmol of the respective amine is added dropwise at 0° C. to asolution of 0.42 mmol of the appropriate biphenylcarboxylic acid, 0.44mmol of HOBT and 0.44 mmol of EDAC in 5 ml of THF and it is stirred atRT for 4 to 12 h. The reaction mixture is diluted with EA and washedwith dilute hydrochloric acid and sodium bicarbonate solution. Afterdrying over magnesium sulfate and concentrating in vacuo, thecorresponding amide is obtained.

EXAMPLE 8a Benzyl[2′-(1-carbamoyl-3-methylbutylcarbamoyl)biphenyl-2-ylmethyl]carbamate

[0440]

[0441] From 0.28 mmol of2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid (precursor6) and L-leucinamide hydrochloride/triethylamine, according to thegeneral working procedure 180 mg of benzyl [2′-(1-carbamoyl-3-methylbutylcarbamoyl)biphenyl-2-ylmethyl]carbamate wereobtained. MS (ES+): m/e=474 (M+1).

EXAMPLE 8b methyl2-{[2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carbonyl]amino}-3-phenylpropionate

[0442]

[0443] From 0.28 mmol of2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid (precursor6) and L-phenylalanine methyl ester hydrochloride/triethylamine,according to the general working procedure 230 mg of methyl2-{[2′-(benzyloxycarbonylaminomethyl)biphenyl-2-carbonyl]amino}-3-phenylpropionatewere obtained. MS (ES+): m/e=523 (M+1).

EXAMPLE 8c 2′-(tert-Butoxycarbonylaminomethyl)biphenyl-2-carboxylic acid(2,4-difluorobenzyl)amide

[0444]

[0445] From 10 mmol of2′-(tert-butoxycarbonylaminomethyl)biphenyl-2-carboxylic acid (precursor7) and 2,4-difluorobenzylamine, according to the general workingprocedure 3.8 g of2′-(tert-butoxycarbonylamino-methyl)biphenyl-2-carboxylic acid(2,4-difluorobenzyl)amide were obtained. MS (ES+): m/e=453 (M+1).

EXAMPLE 8d-8p

[0446] The following products were obtained from2′-(tert-butoxy-carbonylaminomethyl)biphenyl-2-carboxylic acid(precursor 7) and the corresponding amines analogously to Examples8a-8c: Example MS (ES+): No. Structure m/e = M.p. 8d

418 139 8e

418 171 8f

432 161 8g

432 59 8i

431 171 8j

433 165 8k

421 199 8l

397 8m

461 8n

490 8o

432

EXAMPLES 8p-8ac

[0447] The following products were obtained from2′-(benzyloxycarbonylamino-methyl)biphenyl-2-carboxylic acid (precursor6) and the corresponding amines analogously to Examples 8a-8c: ExampleMS (ES+): No. Structure m/e = M.p. 8p

460 119° C. 8q

480 8r

489 8s

471 8x

494 8y

460 8z

524 8aa

466 8ab

466 132° C. 8ac

474

[0448] General Procedure for the Reaction of Aminomethylbiphenyls withIsothiocyanates to Give Thioureas (Examples 9a-9i):

[0449] 0.36 mmol of the respective isothiocyanate dissolved in 0.5 ml ofmethylene chloride is slowly added dropwise at 0° C. to a solution of0.34 mmol of the respective 2′-aminomethylbiphenyl and 41 mg (0.41 mmol)of triethylamine in 5 ml of methylene chloride. After stirring at RT for3 h, the reaction mixture is concentrated in vacuo, the residue isstirred with 25 ml of water and the precipitated product is filtered offwith suction or purified by preparative HPLC.

[0450] The following products, inter alia, were obtained in this way:Example MS (ES+): No. Structure m/e = 9a

483 9c

466 9d

609 9e

534 9f

480 9g

480 9h

537 9i

551

EXAMPLES 10a-10o

[0451] The following products, inter alia, were obtained by coupling2′-(tert-butyloxycarbonylaminomethyl)biphenyl-2-carboxylic acid(precursor 7) with corresponding amines analogously to the methodsdescribed for Example 6 or 8: Example MS (ES+): No. Structure m/e = 10a

384 10b

506 10c

460 10d

498 10e

484 10f

431 10g

446 10h

417 10i

509 10j

422 10k

417 10l

406 10m

434 10n

466 10o

412

EXAMPLES 11a-11r

[0452] General Procedure for the Conversion of the Boc Derivatives ofExamples 10 to Ureas:

[0453] For the removal of the Boc protective group, 1 g of theappropriate compound of Example 10 was added to 10 ml of a 30% solutionof TFA in dichloromethane. The mixture was stirred at RT for 30 min andthe solvent was removed in vacuo on a rotary evaporator. The residue wastaken up in ethyl acetate and washed with saturated sodiumhydrogencarbonate solution. The organic phase was dried over magnesiumsulfate and filtered, and the solvent was removed in vacuo The2′-aminomethyl-biphenyl-2-carboxamides obtained were then reacted withisocyanates to give the corresponding ureas according to the procedurefor Examples 5.

[0454] The following products, inter alia, were obtained in this way: MS(ES+): Example Structure m/e = 11a

480 11b

486 11c

466 11d

504 11e

521 11f

439 11g

437 11h

561 11i

547 11j

585 11k

553 11l

484 11m

519 11n

473 11o

519 11p

502 11q

446 11r

597

[0455] General Working Procedures for the Preparation of CompoundsAccording to the Invention by means of Solid-phase Synthesis:

[0456] The quantitative data in the procedures in each case alwaysrelate to the resin loading, which was determined by UV photometry afterremoval of the Fmoc protective group (see for example“The CombinatorialChemistry Catalog”, Novabiochem).

[0457] General Procedure for the Coupling of α-Fmoc-amino acids to RinkAmide Resin

[0458] A solution of 1.5 equivalents each of HOBT, TOTU, DIPEA and theα-Fmoc amino acid in DMF (5 ml/g of resin) was added to Rink amidepolystyrene resin (loading 1.2 mmol/g) and the mixture was shaken atroom temperature for 12 h. The resin was filtered off and washed 3 timeswith 10 ml each of DMF, once with 10 ml of toluene, once with 10 ml ofmethanol and 3 times with 10 ml of dichloromethane. Determination of theloading according to the Fmoc method showed a loading of 0.9 mmol/g ofcarrier.

[0459] Removal of the Fmoc Protective Group

[0460] For the removal of the Fmoc protective group, the resin waspreswollen in DMF at room temperature for 5 min. After addition of asolution of DMF/piperidine (4 ml/g of resin, 1:1), the mixture wasshaken at room temperature for 20 min. The solution was filtered offwith suction and the process was repeated. The removal of an analyticalsample showed complete reaction according to HPLC/MS investigation.After complete reaction, the resin was washed three times withdichloromethane and employed directly in the coupling.

[0461] General Working Procedure for the Coupling of the Resin-bondedAmino Acids with the 2′-phthalimidomethylbiphenyl-2-carboxylic acid(precursor 2)

[0462] A solution of 12.2 mg (0.09 mmol) of HOBT, 29.5 mg (0.09 mmol) ofTOTU, 16 μl (0.09 mmol) of DIPEA and 0.09 mmol of2′-phthalimido-methylbiphenyl-2-carboxylic acid (precursor 2) in 5 ml ofDMF was added to 100 mg of resin loaded with the amino acid (0.6-0.8mmol/g) and the mixture was shaken at room temperature for 12 h. Theresin was filtered off and washed 3 times with 10 ml each of DMF, oncewith 10 ml of toluene, once with 10 ml of methanol and 3times with 10 mlof dichloromethane.

[0463] General Procedure for the Removal of the Phthalimido ProtectiveGroup on the Carrier

[0464] 5 ml of a 10% strength solution of hydrazine in DMF were added to1 g of resin loaded with the Fmoc-protected amino compound and themixture was shaken at room temperature for 2 h The resin was filteredoff with suction. The resin was then washed 3 times each with 10 ml eachof DMF and dichloromethane. The removal of an analytical sample showedcomplete reaction according to HPLC/MS investigation.

[0465] General Procedure for Coupling with Sulfonyl Chlorides

[0466] A solution of 0.16 ml (0.027 mmol) of DIPEA and 0.027 mmol of thesulfonyl chloride in 5 ml of DMF was added to 100 mg of resin loadedwith the functionalized 2′-aminomethylbiphenyl-2-carboxylic acid and themixture was shaken at room temperature for 12 h. The resin was filteredoff and washed 3 times with 10 ml each of DMF, once with 10 ml oftoluene, once with 10 ml of methanol and 3 times with 10 ml ofdichloromethane.

[0467] General Working Procedure for Removal from the Resin

[0468] For removal, the resin was suspended indichloromethane/trifluoroacetic acid (3 ml/0.1 g of resin) and shakenfor 1 h. The resin was filtered and washed with 1 ml of dichloromethane.The combined removal solution was concentrated in a rotary concentrator.The residue was taken up in dichloromethane and chromatographed onsilica gel using dichloromethane and ethyl acetate or purified bypreparative HPLC.

[0469] The following products, inter alia, were obtained in this way:Example MS (ES+): No. Structure m/e = 12a

542 12b

480 12c

516 12d

534 12e

506 12f

528 12g

564 12h

582 12i

554 12j

522 12k

530 12l

565 12m

556

EXAMPLE 13a2-{[2′-(Benzyloxycarbonylaminomethyl)biphenyl-2-carbonyl]amino}-4-methylpentanoicacid

[0470]

[0471] The compound was obtained from the methyl ester of Example 8r byhydrolysis with potassium hydroxide in methanol/water at 60° C.

EXAMPLES 13b-13e

[0472] The following compounds were obtained by coupling of thecarboxylic acid of Example 13a with the appropriate amines according tothe general method indicated in Example 8: Example MS (ES+): No.Structure m/e = 13b

550 13c

564 13d

556 13e

544

[0473] The following compounds were obtained by hydrogenolytic removalof the Z protective group of the compound of Example 13c and subsequentreaction with the appropriate acid chlorides: Example MS (ES+): No.Structure m/e = 13f

556 13g

554 13h

592

[0474] Starting from the compound of Example 8z, the following compoundwas obtained by hydrolysis and reaction with isopropylamine analogouslyto Examples 13a-13e: Example MS (ES+): No. Structure m/e = 13i

551

[0475] General Procedure for the Coupling of2′-aminomethylbiphenyl-2-carboxylic acid (2,4-difluorobenzyl)amide withCarboxylic Acids to give Garboxamides (Examples 14a-14f):

[0476] 0.27 mmol of the appropriate carboxylic acid was stirred at RTfor 30 min with 0.27 mmol of HOBT and 0.27 mmol of EDAC in 1 ml of THF.0.26 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid(2,4-difluoro-benzyl)amide trifluoroacetate dissolved in 1 ml of THF wasthen added and the mixture was stirred at RT overnight. The reactionmixture was diluted with EA and washed with sodium bicarbonate solutionand water. After concentrating the organic phase, the products werepurified by means of preparative HPLC.

[0477] The following compounds were prepared in this way: Example MS(ES+): No. Structure m/e = 14a

499 14b

503 14c

499 14d

501 14e

515 14f

521

[0478] General Procedure for the Synthesis of Biphenyls by SuzukiCoupling (Examples 15a-15b)

[0479] 58 mg (0.05 mmol) of tetrakistriphenylphosphine palladium and 1mmol of the appropriate bromide were added to dimethoxyethane (10 ml)gassed with argon. After 10 min. 1.5 mmol of the appropriate boronicacid were added and finally 1 ml of a 2 molar sodium carbonate solution(2 mmol). The mixture was heated to reflux under argon for 18 h, cooledand diluted with 30 ml of methylene chloride. The mixture was washedwith water and saturated sodium chloride solution, dried over sodiumsulfate, concentrated and purified by chromatography on silica gel.

EXAMPLE 15a 2′-(tert.-Butyloxycarbonylaminomethyl)-4-nitrobiphenyl-2-carboxylic acid (3-methylbutyl)amide

[0480]

[0481] According to the general procedure, 350 mg (79% yield) of thenitro-substituted compound were obtained as a yellow solid.

EXAMPLE 15b2′-(tert-Butyloxycarbonylaminomethyl)-4-methoxybiphenyl-2-carboxylicacid (3-methylbutyl)amide

[0482]

[0483] According to the general procedure, 170 mg (41% yield) of themethoxy-substituted compound were obtained as a viscous pale oil.

EXAMPLE 16a2′-(tert.-Butyloxycarbonylaminomethyl)-4-aminobiphenyl-2-carboxylic acid(3-methylbutyl)amide

[0484]

[0485] 330 mg (0.75 mmol) of the nitro-substituted compound of Example15a were dissolved in ethyl acetate and hydrogenated under a hydrogenatmosphere (1 bar) using a spatula tipful of 10% palladium on carbon.After 2 h, the mixture was filtered through Celite and the clearsolution was concentrated. Yield: 260 mg (84%).

EXAMPLE 16b2′-(Benzyloxycarbonylaminomethyl)-4-hydroxybiphenyl-2-carboxylic acid(3-methylbutyl)amide

[0486]

[0487] 150 mg (0.35 mmol) of the methoxy-substituted compound of Example15b were dissolved in 5 ml of anhydrous methylene chloride and slowlytreated at −70° C. with 1.4 ml (1.4 mmol) of a 1 molar solution of borontribromide in n-hexane. After 10 min, the reaction solution was slowlywarmed to 0° C. After 2 h at this temperature, it was neutralized withsaturated sodium hydrogencarbonate solution, extracted with a total of40 ml of methylene chloride, dried over sodium sulfate and concentrated.Of the crude product (88 mg) of2′-aminomethyl-4-hydroxybiphenyl-2-carboxylic acid (3-methyl-butyl)amideobtained, 30 mg (0.1 mmol) were dissolved in 3 ml of methylene chlorideand treated with 11 mg (0.11 mmol) of triethylamine and 27 mg (0.11mmol) of benzyloxycarbonyloxysuccinimide. After 3 h, the mixture wasdiluted with methylene chloride, washed with water, and the organicphase was dried over sodium sulfate and purified by RP-HPLC. 8 mg of2′-(benzyloxycarbonylaminomethyl)-4-hydroxybiphenyl-2-carboxylic acid(3-methylbutyl)amide were obtained as a dark oil.

Example 17a {1-[2′-(3-Methyl-butylcarbamoyl)-biphenyl-2-yl]-ethyl}-carbamin acidtert.-butylate

[0488]

[0489] 2.2 g (10 mmol) of N-Boc-(R)-phenethylamine were dissolved in 50ml dry THF, it was cooled down to −78° C., and 14 ml of an 1.5 Msolution of t-butyl lithium in pentane were added drop by drop (21mmol). It was warmed up during 2 h to −20° C. Then 4.5 ml (40 mmol) ofboric acid trimethylate was added, and it was warmed to RT. The solutionwas cooled to 0° C., it was acidified with 10% HCl until pH 6, theaqueous phase was extracted with dichloromethane, the unified organicphases were washed with saturated NaCl-solution, were dried anddistilled off. The boron acid was obtained as a pale yellow solid foam,which was processed without further purification. The Suzuki couplingwas carried out according to the general procedure (see example 15)using 1 mmol of 2-bromo-N-(3-methyl-butyl)-benzamide. Afterchromatograhic purification, 85 mg (0.2 mmol) of the biphenyl resulted.

EXAMPLES 17b -17e

[0490] The enantiomer 17b was obtained analogously to Example 17a. Byremoving the Boc-group and production of the respective carbamates thecompounds 17a and 17b were transformed into the compounds of examples17c - 17e. example MS (ES+): No. structure m/e = 17b

411 17c

445 17d

445 17e

459

[0491] Analogously to the procedures described in examples 1 to 17, thefollowing compounds were synthesized: example MS (ES+): No. structurem/e = 18a

379 18b

427 18c

431 18d

443 18e

451 18f

464 18g

416 18h

478 18i

478 18j

523 18k

457 18l

487 18m

395 18n

433 18o

395 18p

465 18q

466 18r

494 18s

480 18t

487 18u

489 18v

515 18w

487 18x

473 18y

475 18z

443 18aa

433 18ab

459 18ac

432 18ad

478 18ae

566 18af

505 18ag

543 18ah

491 18ai

494

[0492] Pharmacological Investigations

[0493] Kv1.5 channels from humans were expressed in Xenopus oocytes. Forthis, oocytes from Xenopus laevis were first isolated anddefolliculated. RNA encoding Kv1.5 synthesized in vitro was theninjected into these oocytes. After Kv1.5 protein expression for 1-7days, Kv1.5 currents were measured on the oocytes using thetwo-microelectrode voltage clamp technique. The Kv1.5 channels were inthis case as a rule activated using voltage jumps to 0 mV and 40 mVlasting 500 ms. The bath was rinsed with a solution of the followingcomposition: NaCl 96 mM, KCl 2 mM, CaCl₂ 1.8 mM, MgCl₂ 1 mM, HEPES 5 mM(titrated with NaOH to pH 7.4). These experiments were carried out atroom temperature. The following were employed for data acquisition andanalysis: Geneclamp amplifier (Axon Instruments, Foster City, USA) andMacLab D/A converter and software (AD Instruments, Castle Hill,Australia). The substances according to the invention were tested byadding them in different concentrations to the bath solution. Theeffects of the substances were calculated as the percentage inhibitionof the Kv1.5 control current which was obtained when no substance wasadded to the solution. The data were then extrapolated using the Hillequation in order to determine the inhibitory concentration IC₅₀ for therespective substances.

[0494] The following IC₅₀ values were determined in this way for thecompounds listed below: example IC₅₀ example IC₅₀ example IC₅₀ exampleIC₅₀ No. [μM] No. [μM] No. [μM] No. [μM]  1 a   6.1  2 a   2.6 4 a 4.1 6h 3.0 1 b 3.3 2 b 0.8 4 c 1.4  7 a   ˜6.0 1 d 1.0  2 c   0.7   4 d  1.8 8 a   0.3  1 e   0.5 2 d 1.7   4 g  3.4 8 b 0.9 1 f  0.4  2 e   3.4   4h  1.8 8 d 6.4 1 g 0.4 2 f  7.1 4 i  4.7  8 j  4.5 1 h 4.3 2 g 3.3 4 j 7.1 8 k 3.1  1 i  1.7 2 h 2.5   4 k  2.2  8 l  3.5  1 j  0.2  2 i  3.3 4l  0.8  8 m 5.2 1 k 2.4  2 j  2.5 5 a 4.5 8 n 3.7  1 l  1.4 2 k 3.8 5 c7.8 8 o 8.4  1 m 0.7  2 m 2.6   5 d  1.9 8 p 1.4 1 n 1.4 3 d 1.7 5 e 7.28 q 7.3 1 o 4.4 3 k 2.4 6 a 4.4 8 r  1.0 1 r  0.8  3 l  2.6   6 b  1.8 8 s  1.0  1 s  1.7 3 p 1.9 6 c 2.5 8 x 3.3  1 t  1.3 3 r  1.5   6 d 3.1 8 y 2.8 1 u 0.8 3 3.0 6 e 3.6  8 z   1.6  8 aa 0.8   8 ab 1.2   8 ac1.1 9 b 3.0  9 c   2.0 9 f  2.2   9 g  2.2 11 a   2.3 11 b  7.3 11 d 3.3 11 g   7.8 11 h  5.8 11 l    2.7  11 m  3.3 11 n   5.9 11 o  4.4 11p  7.3 12 c   11.2 12 f    11.3 12 g  9.1 12 h  4.8 12 l    10.3 12 m 7.7 13 b  ˜3.0 13 c   1.4 13 d  0.5 13 e  2.8 13 f   3.4 13 g  1.1 13 h 1.4 13 i   1.2 14 a   3.6 14 b  2.7 14 d  2.0 14 e  0.8 14 f   2.5 15 b 3.1 16 b  5.2 18 a  7.2 18 b  0.4 18 c   4.2 18 d  0.4 18 e  1.7 18 f  1.3 18 g  3.9 18 h  0.8 18 i   0.4 18 j    0.7 18 k  3.0  18 m  2.1 18n   0.4 18 o  3.6 18 p  4.7 18 q  3.2 18 r    0.7 18 s    0.9 18 u  1.118 v  0.4  18 w  5.4 18 x  4.6 17 d  1.3 17 e   1.8 17 c  2.1 18 y  1.918 z   1.2  18 aa  0.4 18 ab 1.1  18 ac  10  18 ad   0.3  18 af  5.8 18ah 2.1 18 ai  6.6

We claim:
 1. A compound of the formula I,

in which: R(1) is C(O)OR(9), SO₂R(10), COR(11), C(O)NR(12)R(13) orC(S)NR(12)R(13); R(9) is C_(x)H_(2x)—R(14); x is 0, 1, 2, 3or 4, where xcannot be 0 if R(14) is OR(15) or SO₂Me; R(14) is alkyl having 1, 2, 3,4, 5 or 6 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9, 10 or 11carbon atoms, CF₃, C₂F₅, C₃F₇, CHF₂, OR(15), SO₂Me, phenyl, naphthyl,biphenylyl, furyl, thienyl or an N-containing heteroaromatic having 1,2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, where phenyl, naphthyl,biphenylyl, furyl, thienyl and the N-containing hetero-aromatic areunsubstituted or substituted by 1, 2 or 3 substituents selected from thegroup consisting of F, Cl, Br, I, OCF₃, CF₃, NO₂, CN, COOMe, CONH₂,COMe, NH₂, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1,2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl andmethylsulfonylamino; R(15) is alkyl having 1, 2, 3, 4 or 5 carbon atoms,cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF₃ or phenyl which isunsubstituted or substituted by 1, 2 or 3 substituents selected from thegroup consisting of F, Cl, Br, I, CF₃, NO₂, CN, COOMe, CONH₂, COMe, NH₂,OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl andmethylsulfonylamino; R(10), R(11) and R(12) independently of one anotherare defined as R(9); R(13) is hydrogen, alkyl having 1, 2, 3 or 4 carbonatoms or CF₃; R(2) is hydrogen, alkyl having 1, 2, 3 or 4 carbon atomsor CF₃; R(3) is C_(y)H_(2y)—R(16); y is 0, 1, 2, 3 or 4, where y cannotbe 0 if R(16) is OR(17) or SO₂Me; R(16) is alkyl having 1, 2, 3, 4, 5 or6 carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8, 9, 10 or 11 carbonatoms, CF₃, C₂F₅, C₃F₇, CH₂F, CHF₂, OR(17), SO₂Me, phenyl, naphthyl,furyl, thienyl or an N-containing heteroaromatic having 1, 2, 3, 4, 5,6, 7, 8 or 9 carbon atoms, where phenyl, naphthyl, furyl, thienyl andthe N-containing heteroaromatic are unsubstituted or substituted by 1, 2or 3 substituents selected from the group consisting of F, Cl, Br, I,CF₃, OCF₃, NO₂, CN, COOMe, CONH₂, COMe, NH₂, OH, alkyl having 1, 2, 3 or4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino,sulfamoyl, methylsulfonyl and methylsulfonylamino; R(17) is hydrogen,alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or6 carbon atoms, CF₃, phenyl or 2-, 3- or 4-pyridyl, where phenyl or 2-,3- or 4-pyridyl are unsubstituted or substituted by 1, 2 or 3substituents selected from the group consisting of F, Cl, Br, I, CF₃,OCF₃, NO₂, CN, COOMe, CONH₂, COMe, NH₂, OH, alkyl having 1, 2, 3 or 4carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino,sulfamoyl, methylsulfonyl and methylsulfonylamino; or R(3) isCHR(18)R(19); R(18) is hydrogen or C_(z)H_(2z)—R(16), where R(16) isdefined as indicated above; z is 0, 1, 2or 3; R(19) is COOH, CONH₂,CONR(20)R(21), COOR(22), or CH₂OH; R(20) is hydrogen, alkyl having 1, 2,3, 4 or 5 carbon atoms, C_(v)H_(2v)—CF₃ or C_(w)H_(2w)-phenyl, where thephenyl ring is unsubstituted or substituted by 1, 2 or 3 substitutentsselected from the group consisting of F, Cl, Br, I, CF₃, NO₂, CN, COOMe,CONH₂, COMe, NH₂, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxyhaving 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl,methylsulfonyl and methylsulfonylamino; v is 0, 1, 2 or 3; w is 0, 1, 2or 3; R(21) is hydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms;R(22) is alkyl having 1, 2, 3, 4 or 5 carbon atoms; R(4) is hydrogen,alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or CF₃; or R(3) and R(4)together are a chain of 4 or 5 methylene groups, of which one methylenegroup can be replaced by —O—, —S—, —NH—, —N(methyl)- or —N(benzyl)-;R(5), R(6), R(7) and R(8) independently of one another are hydrogen, F,Cl, Br, I, CF₃, NO₂, CN, COOMe, CONH₂, COMe, NH₂, OH, alkyl having 1, 2,3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino; R(30)and R(31) independently of one another hydrogen or alkyl having 1, 2 or3 carbon atoms; or R(30) and R(31) together form a chain of 2 methylenegroups; or a pharmaceutically acceptable salt thereof.
 2. A compound asclaimed in claim 1, in which R(1) is C(O)OR(9), SO₂R(10), COR(11) orC(O)NR(12)R(13); R(9) is C_(x)H_(2x)—R(14); x is 0, 1, 2, 3 or 4, wherex cannot be 0 if R(14) is OR(15); R(14) is alkyl having 1, 2, 3 or 4carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF₃,C₂F₅, OR(15), phenyl, furyl, thienyl or an N-containing heteroaromatichaving 1, 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms, where phenyl, furyl,thienyl and the N-containing heteroaromatic are unsubstituted orsubstituted by 1, 2 or 3 substituents selected from the group consistingof F, Cl, Br, CF₃, OCF₃, NO₂, CN, COOMe, CONH₂, COMe, NH₂, OH, alkylhaving 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbonatoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;R(15) is alkyl having 1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3,4, 5 or 6 carbon atoms, CF₃ or phenyl, which is unsubstituted orsubstituted by 1, 2 or 3 substituents selected from the group consistingof F, Cl, Br, CF₃, NO₂, CN, COOMe, CONH₂, COMe, OH, alkyl having 1, 2, 3or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R(10),R(11) and R(12) independently of one another are defined as R(9); R(13)is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF₃; R(2) ishydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or CF₃; R(3) isC_(y)H_(2y)—R(16); y is 0, 1, 2, 3 or 4, where y cannot be 0 if R(16) isOR(17); R(16) is alkyl having 1, 2, 3 or 4 carbon atoms, cycloalkylhaving 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF₃, C₂F₅, OR(17), phenyl,furyl, thienyl or an N-containing heteroaromatic having 1, 2, 3, 4, 5,6, 7, 8 or 9 carbon atoms, where phenyl, furyl, thienyl and theN-containing heteroaromatic are unsubstituted or substituted by 1, 2 or3 substituents selected from the group consisting of F, Cl, Br, CF₃,OCF₃, NO₂, CN, COOMe, CONH₂, COMe, NH₂, OH, alkyl having 1, 2, 3 or 4carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino,sulfamoyl, methylsulfonyl and methylsulfonylamino; R(17) is alkyl having1, 2, 3, 4 or 5 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbonatoms, CF₃, phenyl or 2-, 3-, or 4-pyridyl, where phenyl or 2-, 3- or4-pyridyl are unsubstituted or substituted by 1, 2 or 3 substituentsselected from the group consisting of F, Cl, Br, CF₃, OCF₃, NO₂, CN,COOMe, CONH₂, COMe, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxyhaving 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl,methylsulfonyl and methylsulfonylamino; or R(3) is CHR(18)R(19); R(18)is hydrogen or C_(z)H_(2z)—R(16), where R(16) is defined as indicated inclaim 1 above; z is 0, 1, 2 or 3; R(19) is CONH₂, CONR(20)R(21),COOR(22), CH₂OH; R(20) is hydrogen, alkyl having 1, 2, 3, 4 or 5 carbonatoms, C_(v)H_(2v)—CF₃ or C_(w)H_(2w)-phenyl, where the phenyl ring isunsubstituted or substituted by 1, 2 or 3 substituents selected from thegroup consisting of F, Cl, Br, CF₃, OCF₃, NO₂, CN, COOMe, CONH₂, COMe,NH₂, OH, alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3or 4 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl andmethylsulfonylamino; v is 0, 1, 2 or 3; w is 0, 1, 2 or 3; R(21) ishydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms; R(22) is alkylhaving 1, 2, 3, 4 or 5 carbon atoms; R(4) is hydrogen, alkyl having 1,2, 3, 4, 5 or 6 carbon atoms or CF₃; and R(5), R(6), R(7) and R(8)independently of one another are hydrogen, F, Cl, Br, CF₃, NO₂, CN,COOMe, CONH₂, COMe, NH₂, OH, alkyl having 1, 2, 3 or 4 carbon atoms,alkoxy having 1, 2, 3 or 4 carbon atoms, dimethylamino, sulfamoyl,methylsulfonyl or methylsulfonylamino; R(30) and R(31) independently ofone another hydrogen or alkyl having 1, 2 or 3 carbon atoms; or R(30)and R(31) together form a chain of 2 methylene groups.
 3. A compound asclaimed in claim 2, in which: R(1) is C(O)OR(9), SO₂R(10), COR(11) orC(O)NR(12)R(13); R(9) is C_(x)H_(2x)—R(14); x is 0, 1, 2, 3 or 4, wherex cannot be 0 if R(14) is OR(15); R(14) is cycloalkyl having 3, 4, 5, 6,7, 8 or 9 carbon atoms, CF₃, OR(15), phenyl, furyl, thienyl or anN-containing heteroaromatic having 3, 4 or 5 carbon atoms, where phenyl,furyl, thienyl and the N-containing heteroaromatic are unsubstituted orsubstituted by 1 or 2 substituents selected from the group consisting ofF, Cl, Br, CF₃, OCF₃, CN, COOMe, CONH₂, COMe, OH, alkyl having 1, 2 or 3carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino,sulfamoyl, methylsulfonyl and methylsulfonylamino; R(15) is alkyl having1 or 2 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF₃ orphenyl, which is unsubstituted or substituted by 1 or 2 substituentsselected from the group consisting of F, Cl, Br, CF₃, CN, COOMe, CONH₂,COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl andmethylsulfonylamino; R(10), R(11) and R(12) independently of one anotherare defined as R(9); R(13) is hydrogen; R(2) is hydrogen or alkyl having1, 2 or 3 carbon atoms; R(3) is CHR(18)R(19); R(18) is hydrogen orC_(z)H_(2z)—R(16); z is 0, 1, 2 or 3; R(19) is CONH₂, CONR(20)R(21),COOR(22) or CH₂OH; R(20) is hydrogen, alkyl having 1, 2, 3, 4 or 5carbon atoms, C_(v)H_(2v)—CF₃ or C_(w)H_(2w)-phenyl, where the phenylring is unsubstituted or substituted by 1, 2 or 3 substituents selectedfrom the group consisting of F, Cl, Br, CF₃, OCF₃, CN, COOMe, CONH₂,COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl andmethylsulfonylamino; v is 0, 1, 2 or 3; w is 0, 1, 2 or 3; R(21) ishydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms; R(22) is alkylhaving 1, 2, 3, 4 or 5 carbon atoms; R(16) is alkyl having 1, 2 or 3carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF₃,OR(17), phenyl, furyl, thienyl or an N-containing heteroaromatic having3, 4 or 5 carbon atoms, where phenyl, furyl, thienyl and theN-containing heteroaromatic are unsubstituted or substituted by 1 or 2substitutents selected from the group consisting of F, Cl, Br, CF₃,OCF₃, CN, COOMe, CONH₂, COMe, NH₂, OH, alkyl having 1, 2 or 3 carbonatoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl,methylsulfonyl and methylsulfonylamino; R(17) is alkyl having 1, 2, 3 or4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF₃, phenylor 2-, 3- or 4-pyridyl, where phenyl or 2-, 3- or 4-pyridyl areunsubstituted or substituted by 1, 2 or 3 substituents selected from thegroup consisting of F, Cl, Br, CF₃, OCF₃, CN, COOMe, CONH₂, COMe, OH,alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl andmethylsulfonylamino; R(4) is hydrogen or alkyl having 1 or 2 carbonatoms; and R(5), R(6), R(7) and R(8) independently of one another arehydrogen, F, Cl, Br, CF₃, CN, COOMe, CONH₂, COMe, NH₂, OH, alkyl having1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms,dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino; R(30)and R(31) independently of one another are hydrogen or methyl; or R(30)and R(31) together form a chain of 2 methylene groups.
 4. A compound asclaimed in claim 2, in which: R(1) is C(O)OR(9), SO₂R(10), COR(11) orC(O)NR(12)R(13); R(9) is C_(x)H_(2x)—R(14); x is 0, 1, 2, 3 or 4, wherex cannot be 0 if R(14) is OR(15); R(14) is alkyl having 1, 2, 3 or 4carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF₃,OR(15), phenyl, furyl, thienyl or an N-containing heteroaromatic having3, 4 or 5 carbon atoms, where phenyl, furyl, thienyl and theN-containing heteroaromatic are unsubstituted or substituted by 1 or 2substituents selected from the group consisting of F, Cl, Br, CF₃, OCF₃,CN, COOMe, CONH₂, COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxyhaving 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl andmethylsulfonylamino; R(15) is alkyl having 1 or 2 carbon atoms,cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF₃ or phenyl, which isunsubstituted or substituted by 1 or 2 substituents selected from thegroup consisting of F, Cl, Br, CF₃, CN, COOMe, CONH₂, COMe, OH, alkylhaving 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms,dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R(10),R(11)and R(12) independently of one another are defined as R(9); R(13)is hydrogen; R(2) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;R(3) is C_(y)H_(2y)—R(16); y is 0, 1, 2, 3 or 4, where y cannot be 0 ifR(16) is OR(17); R(16) is alkyl having 1, 2 or 3 carbon atoms,cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF₃, OR(17),phenyl, furyl, thienyl or an N-containing heteroaromatic having 3, 4 or5 carbon atoms, where phenyl, furyl, thienyl and the N-containingheteroaromatic are unsubstituted or substituted by 1 or 2 substituentsselected from the group consisting of F, Cl, Br, CF₃, OCF₃, CN, COOMe,CONH₂, COMe, NH₂, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl andmethylsulfonylamino; R(17) is alkyl having 1, 2, 3, 4 or 5 carbon atoms,cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF₃, phenyl or 2-, 3- or4-pyridyl, where phenyl or 2-, 3- or 4-pyridyl are unsubstituted orsubstituted by 1, 2 or 3 substituents selected from the group consistingof F, Cl, Br, CF₃, OCF₃, NO₂, CN, COOMe, CONH₂, COMe, OH, alkyl having1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbon atoms,dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R(4)is hydrogen or alkyl having 1 or 2 carbon atoms; R(5), R(6), R(7) andR(8) independently of one another are hydrogen, F, Cl, Br, CF₃, CN,COOMe, CONH₂, COMe, NH₂, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxyhaving 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl ormethylsulfonylamino; R(30) and R(31) independently of one another arehydrogen or methyl; or R(30) and R(31) together form a chain of 2methylene groups.
 5. A compound as claimed in claim 4, in which: R(1) isC(O)OR(9), SO₂R(10), COR(11) or C(O)NR(12)R(13); R(9) isC_(x)H_(2x)—R(14); x is 0, 1, 2 or 3; R(14) is alkyl having 1, 2, 3 or 4carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF₃,phenyl or pyridyl, where phenyl and pyridyl are unsubstituted orsubstituted by 1 or 2 substituents selected from the group consisting ofF, Cl, CF₃, OCF₃, OH, alkyl having 1, 2 or 3 carbon atoms and alkoxyhaving 1 or 2 carbon atoms; R(10), R(11) and R(12) independently of oneanother are defined as R(9); R(13) is hydrogen; R(2) is hydrogen; R(3)is C_(y)H_(2y)—R(16); y is 0, 1 or2; R(16) is alkyl having 1, 2 or 3carbon atoms, cycloalkyl having 5 or 6 carbon atoms, CF₃, phenyl orpyridyl, where phenyl and pyridyl are unsubstituted or substituted by 1or 2 substituents selected from the group consisting of F, Cl, CF₃,OCF₃, OH, alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2carbon atoms; R(4) is hydrogen; R(5), R(6), R(7) and R(8) independentlyof one another are hydrogen, F, CF₃, CN, COOMe, CONH₂, NH₂, OH, alkylhaving 1, 2 or 3 carbon atoms or alkoxy having 1 or 2 carbon atoms;R(30) and R(31) independently of one another hydrogen or methyl; orR(30) and R(31) together form a chain of 2 methylene groups;
 6. Acompound as claimed in claim 5, in which: R(1) is C(O)OR(9) or COR(11);R(9) is C_(x)H_(2x)—R(14); x is 0, 1, 2 or 3; R(14) is cycloalkyl having5 or 6 carbon atoms or phenyl, where phenyl is unsubstituted orsubstituted by 1 or 2 substituents selected from the group consisting ofF, Cl, CF₃, OCF₃, alkyl having 1, 2 or 3 carbon atoms and alkoxy having1 or 2 carbon atoms; R(11) is defined as R(9); R(2) is hydrogen; R(3) isC_(y)H_(2y)—R(16); y is 0, 1 or 2; R(16) is alkyl having 1, 2 or 3carbon atoms, cycloalkyl having 5 or 6 carbon atoms, CF₃, phenyl orpyridyl where phenyl and pyridyl are unsubstituted or substituted by 1or 2 substituents selected from the group consisting of F, Cl, CF₃,OCF₃, alkyl having 1, 2 or 3 carbon atoms and alkoxy having 1 or 2carbon atoms; R(4) is hydrogen; R(5), R(6), R(7) and R(8) independentlyof one another are hydrogen, F, CF₃, alkyl having 1, 2 or 3 carbon atomsor alkoxy having 1 or 2 carbon atoms; R(30) and R(31) are hydrogen;
 7. Apharmaceutical composition, comprising an effective amount of at leastone compound as claimed in claim 1 together with a pharmaceuticallyacceptable vehicle or additive.
 8. A pharmaceutical composition asclaimed in claim 7, which further comprises one or more otherpharmacologically active compounds.
 9. A method for the prophylaxis ortherapy of a K⁺ channel-mediated illness, which comprises administeringto a host in need of the prophylaxis or therapy an effective amount of acompound as claimed in claim
 1. 10. A method for the therapy orprophylaxis of a cardiac arrythmia which can be eliminated by actionpotential prolongation, which comprises administering to a host in needof the therapy or prophylaxis an effective amount of a compound asclaimed in claim
 1. 11. A method for the therapy or prophylaxis of are-entry arrythmia, which comprises administering to a host in need ofthe therapy or prophylaxis an effective amount of a compound as claimedin claim
 1. 12. A method for the therapy or prophylaxis of asupraventricular arrythmia, which comprises administering to a host inneed of the therapy or prophylaxis an effective amount of a compound asclaimed in claim
 1. 13. A method for the therapy or prophylaxis ofatrial fibrillation or atrial flutter, which comprises administering toa host in need of the therapy or prophylaxis an effective amount of acompound as claimed in claim
 1. 14. A method for terminating existingatrial fibrillation or flutter to restore sinus rhythm, which comprisesadministering to a host in need of the termination an effective amountof a compound as claimed in claim
 1. 15. A pharmaceutical composition asclaimed in claim 7, which further comprises an effective amount of anIKr channel blocker.
 16. A pharmaceutical composition as claimed inclaim 7, which further comprises an effective amount of an IKs channelblocker.
 17. A pharmaceutical composition as claimed in claim 7, whichfurther comprises an effective amount of a beta-blocker.
 18. A compoundas claimed in claim 1, in which: R(1) is C(O)OR(9), SO₂R(10), COR(11) orC(O)NR(12)R(13); R(9) is C_(x)H_(2x)—R(14); x is 0, 1, 2, 3 or 4, wherex cannot be 0 if R(14) is OR(15); R(14) is cycloalkyl having 3, 4, 5, 6,7, 8 or 9 carbon atoms, CF₃, OR(15), phenyl, furyl, thienyl or anN-containing heteroaromatic having 3, 4 or 5 carbon atoms, where phenyl,furyl, thienyl and the N-containing heteroaromatic are unsubstituted orsubstituted by 1 or 2 substituents selected from the group consisting ofF, Cl, Br, CF3, OCF₃, CN, COOMe, CONH₂, COMe, OH, alkyl having 1, 2 or 3carbon atoms, alkoxy having 1 or 2 carbon atoms, dimethylamino,sulfamoyl, methylsulfonyl and methylsulfonylamino; R(15) is alkyl having1 or 2 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF₃ orphenyl, which is unsubstituted or substituted by 1 or 2 substituentsselected from the group consisting of F, Cl, Br, CF₃, CN, COOMe, CONH₂,COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl andmethylsulfonylamino; R(10), R(11) and R(12) independently of one anotherare defined as R(9); R(13) is hydrogen; R(2) is hydrogen or alkyl having1, 2 or 3 carbon atoms; R(3) is CHR(18)R(19); R(18) is hydrogen orC_(z)H_(2z)—R(16); z is 0, 1, 2 or 3; R(19) is CONH₂, CONR(20)R(21),COOR(22) or CH₂OH; R(20) is hydrogen, alkyl having 1, 2, 3, 4 or 5carbon atoms, C_(v)H_(2v)—CF₃ or C_(w)H_(2w)-phenyl, where the phenylring is unsubstituted or substituted by 1, 2 or 3 substituents selectedfrom the group consisting of F, Cl, Br, CF₃, OCF₃, CN, COOMe, CONH₂,COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having 1 or 2carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl andmethylsulfonylamino; v is 0, 1, 2 or 3; w is 0, 1, 2 or 3; R(21) ishydrogen or alkyl having 1, 2, 3, 4 or 5 carbon atoms; R(22) is alkylhaving 1, 2, 3, 4 or 5 carbon atoms; R(16) is alkyl having 1, 2 or 3carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF₃,OR(17), phenyl, furyl, thienyl or an N-containing heteroaromatic having3, 4 or 5 carbon atoms, where phenyl, furyl, thienyl and theN-containing heteroaromatic are unsubstituted or substituted by 1 or 2substitutents selected from the group consisting of F, Cl, Br, CF₃,OCF₃, CN, COOMe, CONH₂, COMe, NH₂, OH, alkyl having 1, 2 or 3 carbonatoms, alkoxy having 1 or 2 carbon atoms, dimethylamino, sulfamoyl,methylsulfonyl and methylsulfonylamino; R(17) is alkyl having 1, 2, 3 or4 carbon atoms, cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF₃, phenylor 2-, 3- or 4-pyridyl, where phenyl or 2-, 3- or 4-pyridyl areunsubstituted or substituted by 1, 2 or 3 substituents selected from thegroup consisting of F, Cl, Br, CF₃, OCF₃, CN, COOMe, CONH₂, COMe, OH,alkyl having 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl andmethylsulfonylamino; R(4) is hydrogen or alkyl having 1 or 2 carbonatoms; and R(5), R(6), R(7) and R(8) independently of one another arehydrogen, F, Cl, Br, CF₃, CN, COOMe, CONH₂, COMe, NH₂, OH, alkyl having1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms,dimethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino; R(30)and R(31) independently of one another are hydrogen or methyl; or R(30)and R(31) together form a chain of 2 methylene groups.
 19. A compound asclaimed in claim 1, in which: R(1) is C(O)OR(9), SO₂R(10), COR(11) orC(O)NR(12)R(13); R(9) is C_(x)H_(2x)—R(14); x is 0, 1, 2, 3 or 4, wherex cannot be 0 if R(14) is OR(15); R(14) is alkyl having 1, 2, 3 or4carbon atoms, cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF₃,OR(15), phenyl, furyl, thienyl or an N-containing heteroaromatic having3, 4 or 5 carbon atoms, where phenyl, furyl, thienyl and theN-containing heteroaromatic are unsubstituted or substituted by 1 or 2substituents selected from the group consisting of F, Cl, Br, CF₃, OCF₃,CN, COOMe, CONH₂, COMe, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxyhaving 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl andmethylsulfonylamino; R(15) is alkyl having 1 or 2 carbon atoms,cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF₃ or phenyl, which isunsubstituted or substituted by 1 or 2 substituents selected from thegroup consisting of F, Cl, Br, CF₃, CN, COOMe, CONH₂, COMe, OH, alkylhaving 1, 2 or 3 carbon atoms, alkoxy having 1 or 2 carbon atoms,dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino; R(10),R(11) and R(12) independently of one another are defined as R(9); R(13)is hydrogen; R(2) is hydrogen or alkyl having 1, 2 or 3 carbon atoms;R(3) is C_(y)H_(2y)—R(16); y is 0, 1, 2, 3 or 4, where y cannot be 0 ifR(16) is OR(17); R(16) is alkyl having 1, 2 or 3 carbon atoms,cycloalkyl having 3, 4, 5, 6, 7, 8 or 9 carbon atoms, CF₃, OR(17),phenyl, furyl, thienyl or an N-containing heteroaromatic having 3, 4 or5 carbon atoms, where phenyl, furyl, thienyl and the N-containingheteroaromatic are unsubstituted or substituted by 1 or 2 substituentsselected from the group consisting of F, Cl, Br, CF₃, OCF₃, CN, COOMe,CONH₂, COMe, NH₂, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxy having1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl andmethylsulfonylamino; R(17) is alkyl having 1, 2, 3, 4 or 5 carbon atoms,cycloalkyl having 3, 4, 5 or 6 carbon atoms, CF₃, phenyl or 2-, 3- or4-pyridyl, where phenyl or 2-, 3- or 4-pyridyl are unsubstituted orsubstituted by 1, 2 or 3 substituents selected from the group consistingof F, Cl, Br, CF_(3,) OCF₃, NO₂, CN, COOMe, CONH₂, COMe, OH, alkylhaving 1, 2, 3 or 4 carbon atoms, alkoxy having 1, 2, 3 or 4 carbonatoms, dimethylamino, sulfamoyl, methylsulfonyl and methylsulfonylamino;R(4) is hydrogen or alkyl having 1 or 2 carbon atoms; R(5), R(6), R(7)and R(8) independently of one another are hydrogen, F, Cl, Br, CF₃, CN,COOMe, CONH₂, COMe, NH₂, OH, alkyl having 1, 2 or 3 carbon atoms, alkoxyhaving 1 or 2 carbon atoms, dimethylamino, sulfamoyl, methylsulfonyl ormethylsulfonylamino; R(30) and R(31) independently of one another arehydrogen or methyl; or R(30) and R(31) together form a chain of 2methylene groups.